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Cited by 63Thyroid Disorders and TreatmentsAdvanced Drug Delivery SystemsDrug Solubulity and Delivery Systems

Levothyroxine: conventional and novel drug delivery formulations.

Open access
Liu, Hanqing, Li, Wei, Zhang, Wen, Sun, Shengrong, Chen, Chuang·2023·Endocrine Reviews
DOI 10.1210/endrev/bnac030PMC PMC10166268
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Abstract

Although levothyroxine is one of the most prescribed medications in the world, its bioavailability has been reported to be impaired by many factors, including interfering drugs or foods and concomitant diseases, and persistent hypothyroidism with a high dose of levothyroxine is thus elicited. Persistent hypothyroidism can also be induced by noninterchangeability between formulations and poor compliance. To address these issues some strategies have been developed. Novel formulations (liquid solutions and soft gel capsules) have been designed to eliminate malabsorption. Some other delivery routes (injections, suppositories, sprays, and sublingual and transdermal administrations) are aimed at circumventing different difficulties in dosing, such as thyroid emergencies and dysphagia. Moreover, nanomaterials have been used to develop delivery systems for the sustained release of levothyroxine to improve patient compliance and reduce costs. Some delivery systems encapsulating nanoparticles show promising release profiles. In this review, we first summarize the medical conditions that interfere with the bioavailability of oral levothyroxine and discuss the underlying mechanisms and treatments. The efficacy of liquid solutions and soft gel capsules are systematically evaluated. We further summarize the novel delivery routes for levothyroxine and their possible applications. Nanomaterials in the levothyroxine field are then discussed and compared based on their load and release profile. We hope the article provides novel insights into the drug delivery of levothyroxine.

AI snapshot

Written from the paper’s full text.

TL;DR

This review summarizes conventional levothyroxine (LT4) delivery and newer formulations/routes intended to overcome malabsorption, drug/food interactions, and nonadherence. Liquid solutions and soft gel capsules are the most clinically advanced alternatives, while injectable, rectal, sublingual, transdermal, and nanomaterial-based systems remain less established.

Key findings

  • LT4 tablets account for more than 95% of LT4 prescriptions, but an estimated 30% to 50% of LT4-treated patients are undertreated or overtreated; refractory hypothyroidism is defined as persistent TSH elevation despite >1.9 µg/kg/day, and more than 50% of LT4-treated patients take >1 other drug.
  • Liquid solutions and soft gel capsules can circumvent malabsorption: in calcium/iron coingestion, liquid LT4 reduced TSH versus tablets (7.48 ± 5.8 vs 1.95 ± 1.3 mU/L, P < .001); in PPI users, liquid LT4 reduced TSH versus tablets (1.7 ± 1.0 vs 5.4 ± 4.3 mU/L, P < .001); a meta-analysis of 6 prospective studies found lower TSH with liquid LT4 (4.23 mIU/L, 95% CI 3.69-4.77) than tablets at the same dose.
  • Alternative routes include IV LT4 for myxedema/thyroid emergencies, IM and SC injections as sustained-release options, rectal suppositories (often requiring an additional 100% of the dose or more), and sublingual, respiratory, and transdermal approaches; nanomaterial systems include a poly(caprolactone) SC implant loading ∼40 mg LT4 with average release 30 to 100 µg/day and 8% to 20% cumulative release after 98 days in vitro, and poly-zinc-liothyronine showing ∼30% lower Cmax and ∼6-hour later Tmax than conventional T3.
  • Combined T4/T3 therapy is generally not recommended due to low-quality evidence; a propensity-matched study of 5342 patients in Korea associated longer LT3 use with increased heart failure (incidence rate ratio = 1.664, P = .049) and stroke (incidence rate ratio = 1.757, P = .025).

Methods

  • Narrative review synthesizing literature on LT4 absorption and metabolism, causes of impaired oral bioavailability, and conventional and novel drug delivery formulations/routes.
  • Sources include clinical trials, meta-analyses, case reports, real-world studies, and in vitro/animal studies; the review presents tables and figures but describes no primary data collection.
  • No systematic search strategy, formal risk-of-bias assessment, or quantitative synthesis by the review authors is described.

Limitations

  • Stated: among 31 included articles on LT4 formulations, 14 were case reports or case series, 5 were retrospective cohort studies, 2 were prospective cohort studies, and 8 were prospective pre–post self-control studies; only 2 were well-designed randomized crossover studies, with generally low evidence and high reporting bias.
  • Stated: studies were conducted in a limited number of countries, and common weaknesses included lack of washout periods, nonstandardized interventions, mixed hypothyroidism etiologies and target thyroid hormone ranges, selective outcome reporting, and unavailable long-term effects.
  • Evident: as a narrative review, it lacks a systematic search and formal evidence appraisal; many nanomaterial and alternative-route findings are limited to in vitro or animal studies, and clinical translation remains unproven.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1210/endrev/bnac030

Cites

272 of 272 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 375 cited sources checked · 0 supported · 0 flagged

  • Premisecitation

    Levothyroxine (LT4) is the mainstay therapy for hypothyroidism.

    “Levothyroxine (LT4) is the mainstay therapy for hypothyroidism, but its bioavailability can be hampered by many conditions, such as concomitant diseases, interfering medications and foods, switch of brands, and noncompliance”
    • Also stated in: § Abstract · plain
      “synthesized levothyroxine (LT4) has gradually replaced desiccated thyroid extracts (DTEs) and has become the mainstay therapy for hypothyroidism (3).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [3] McAninch, 2016, The history and future of treatment of hypothyroidism, Ann Intern Med source

      Not checked in the free run.

  • Premisenone given

    Some concomitant diseases, such as atrophic gastritis, lactose intolerance, and celiac disease, might impair the bioavailability of oral LT4.

    “Some concomitant diseases, such as atrophic gastritis, lactose intolerance, and celiac disease might also impair the bioavailability of oral LT4.”
    Quote in the paperNot a substantial claim
  • Premisecitation

    The tablet form is the predominant preparation of LT4, accounting for more than 95% of LT4 prescriptions.

    “The tablet form is the predominant preparation of LT4, accounting for more than 95% of LT4 prescriptions (43).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [43] Vaisman, 2001, Comparative bioavailability of two oral L-thyroxine formulations after multiple dose administration in patients with hypothyroidism and its relation with therapeutic endpoints and dissolution profiles, Arzneimitt Forsch Drug Res

      Not checked in the free run.

  • Premisereasoning

    LT4 bioavailability can be impaired by many factors, including interfering drugs or foods, concomitant diseases, brand switches, and noncompliance.

    “Although levothyroxine is one of the most prescribed medications in the world, its bioavailability has been reported to be impaired by many factors, including interfering drugs or foods and concomitant diseases, and persistent hypothyroidism with a high dose of levothyroxine is thus elicited.”
    • Also stated in: § Abstract · plain
      “Levothyroxine (LT4) is the mainstay therapy for hypothyroidism, but its bioavailability can be hampered by many conditions, such as concomitant diseases, interfering medications and foods, switch of brands, and noncompliance”
    Quote in the paperSubstantial claim
  • Premisenone given

    Novel formulations (liquid solutions and soft gel capsules) have been designed to eliminate malabsorption.

    “Novel formulations (liquid solutions and soft gel capsules) have been designed to eliminate malabsorption.”
    Quote in the paperNot a substantial claim
  • Classified as probably not a substantial claim. 41
  • May combine two claims. 102
  • The quote only partly states this claim. 1

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisenone given

    Patients are initially prescribed LT4 at 1.6 to 1.8 μg/kg body weight/day and are tested for thyroid function every 6 to 8 weeks.

    “In general, patients are initially prescribed a dose of 1.6 to 1.8 µg/kg body weight/day and are tested for thyroid function every 6 to 8 weeks.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Patients may sometimes miss a dose or ingest LT4 with breakfast for convenience, which is observed in 30% to 70% of patients.

    “Patients may sometimes miss a dose or ingest LT4 with breakfast for convenience, which is observed in 30% to 70% of patients (9, 10).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [9] Crilly, 2004, Thyroxine adherence in primary hypothyroidism, Lancet source

      Not checked in the free run.

    • cites [10] Kumar, 2019, Adherence to levothyroxine tablet in patients with hypothyroidism, Cureus

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Hypothyroidism is mainly induced by autoimmune thyroid diseases and thyroidectomy.

    “Hypothyroidism is mainly induced by autoimmune thyroid diseases and thyroidectomy (1, 2).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [1] Chaker, 2017, Hypothyroidism, Lancet source

      Not checked in the free run.

    • cites [2] Canaris, 2000, The Colorado thyroid disease prevalence study, Arch Intern Med source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The daily dose of LT4 is determined by lean body mass, while age, the etiology of hypothyroidism, comorbidities, and other factors also exert effects.

    “The daily dose of LT4 is determined by the lean body mass, while age, the etiology of hypothyroidism, comorbidities, and other factors also exert effects (7).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [7] Jonklaas, 2022, Optimal thyroid hormone replacement, Endocr Rev source

      Not checked in the free run.

  • May combine two claims.

    Premisereasoning

    A switch of brand or generic LT4 and improper storage have been reported to cause TSH fluctuation in patients, which may be attributed to different pharmacokinetic profiles due to excipients.

    “A switch of brand or generic LT4 and improper storage have also been reported to cause TSH fluctuation in patients, which may be attributed to different pharmacokinetic profiles due to excipients.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    Some delivery systems encapsulating nanoparticles show promising release profiles.

    “Some delivery systems encapsulating nanoparticles show promising release profiles.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisenone given

    Persistent hypothyroidism can be induced by noninterchangeability between formulations and poor compliance.

    “Persistent hypothyroidism can also be induced by noninterchangeability between formulations and poor compliance.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Premisenone given

    Some other delivery routes (injections, suppositories, sprays, and sublingual and transdermal administrations) are aimed at circumventing different difficulties in dosing, such as thyroid emergencies and dysphagia.

    “Some other delivery routes (injections, suppositories, sprays, and sublingual and transdermal administrations) are aimed at circumventing different difficulties in dosing, such as thyroid emergencies and dysphagia.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    The leading cause of refractory hypothyroidism is interfering medications, since more than 50% of LT4-treated patients are concurrently taking more than 1 drug for other medical conditions.

    “The leading cause of refractory hypothyroidism is interfering medications, since more than 50% of LT4-treated patients are concurrently taking >1 drug for other medical conditions (8).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [8] Irving, 2015, Drugs that interact with levothyroxine: an observational study from the Thyroid Epidemiology, Audit and Research Study (TEARS), Clin Endocrinol (Oxf) source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The small intestine is proposed to be the predominant site for LT4 absorption, as no uptake of LT4 was detected in a patient with no jejunum or ileum.

    “As no uptake of LT4 was detected in a patient with no jejunum or ileum (19), the small intestine is proposed to be the predominant site for LT4 absorption.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [19] Hays, 1991, Localization of human thyroxine absorption, Thyroid source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The dissolution-pH profile of LT4 tablets is V-shaped: solubility at 30 minutes is approximately 100% at pH 1.2 and 2.4, decreases to less than 60% at pH 4.0, reaches a nadir at pH 5.0 where dissolution at 60 minutes is less than 40%, and increases to 80% to 85% at pH 8.0.

    “As revealed in in vitro studies by Kocic et al and Pabla et al, the dissolution–pH profile is V-shaped (15, 16). The solubility of LT4 tablets at 30 minutes is approximately 100% at pH 1.2 and 2.4. Its solubility decreases substantially to less than 60% at pH 4.0, regardless of the brand. The nadir is reached at pH 5.0, where the percentage of dissolution at 60 minutes decreases to less than 40%.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [15] Kocic, 2011, An investigation into the influence of experimental conditions on in vitro drug release from immediate-release tablets of levothyroxine sodium and its relation to oral bioavailability, AAPS PharmSciTech source

      Not checked in the free run.

    • cites [16] Pabla, 2009, A comparative pH-dissolution profile study of selected commercial levothyroxine products using inductively coupled plasma mass spectrometry, Eur J Pharm Biopharm source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    After absorption, most LT4 molecules are transported via the mesenteric and portal veins to the liver, where 17% of absorbed LT4 is estimated to be taken up.

    “After absorption, most LT4 molecules are transported via the mesenteric and portal veins to the liver, where 17% of absorbed LT4 is estimated to be taken up (29).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [29] Choe, 1995, Absorption of oral thyroxine, Endocrinologist source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    A physiological gastric pH (1.0-3.0) is essential for tablet dissolution, which removes the sodium ion and converts LT4 into a lipophilic molecule.

    “A physiological gastric pH (1.0-3.0) is essential for tablet dissolution, which removes the sodium ion and converts LT4 into a lipophilic molecule.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    A 20% decrease in T4 can increase TSH levels by as much as 2-fold, particularly in patients with no thyroid remnant, as partially functioning thyroids can serve as a buffer.

    “A 20% decrease in T4 can increase TSH levels by as much as 2-fold, particularly in patients with no thyroid remnant, as partially functioning thyroids can serve as a buffer (37).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [37] Hoermann, 2017, Recent advances in thyroid hormone regulation: toward a new paradigm for optimal diagnosis and treatment, Front Endocrinol (Lausanne) source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    The skin, respiratory tract, and oral cavity can also be alternative routes for drug delivery.

    “The skin, respiratory tract, and oral cavity can also be alternative routes for drug delivery.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    Nanomaterials have been used to develop sustained-release drug delivery systems for LT4.

    “Moreover, nanomaterials have been used to develop sustained-release drug delivery systems for LT4.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    These novel preparations potentially circumvent malabsorption induced by interfering medications and concomitant diseases and improve patient adherence.

    “These preparations potentially circumvent malabsorption induced by interfering medications and concomitant diseases and improve patient adherence.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisenone given

    In the liver, some circulating LT4 molecules undergo conjugation, mainly glucuronidation and sulfation, and the conjugated T4 is then secreted with bile into the gut.

    “In the liver, some circulating LT4 molecules undergo conjugation, which enhances their water solubility. The main forms of conjugation of T4 produced in the liver are glucuronidation and sulfation. The conjugated T4 is then secreted with bile into the gut.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    In 4 healthy volunteers, overall absorption of LT4 ranged from 60% to 80%; specifically, 15 ± 5% was absorbed in the duodenum, 29 ± 14% in the jejunum, and 24 ± 11% in the ileum.

    “An experiment in 4 healthy volunteers showed overall absorption ranging from 60% to 80%. Specifically, 15 ± 5% was absorbed in the duodenum, 29 ± 14% in the jejunum, and 24 ± 11% in the ileum.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [20] Hays, 1968, Absorption of oral thyroxine in man, J Clin Endocrinol Metab source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Upon entry into the systemic circulation, ∼99.8% of T4 and T3 are bound to serum carriers, such as thyroxine-binding globulin (TBG), albumin, and transthyretin; TBG binds more than 80% of thyroid hormones.

    “Upon entry into the systemic circulation, ∼99.8% of T4 and its biologically active metabolite, T3, are bound to serum carriers, such as thyroxine-binding globulin (TBG), albumin, and transthyretin (33). TBG binds more than 80% of THs.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [33] Ianiro, 2014, Levothyroxine absorption in health and disease, and new therapeutic perspectives, Eur Rev Med Pharmacol Sci

      Not checked in the free run.

  • May combine two claims.

    Premisereasoning

    Plasma carriers facilitate the circulation of drugs, stabilize the molecules, and prevent their renal clearance.

    “Plasma carriers facilitate the circulation of drugs, stabilize the molecules, and prevent their renal clearance.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    After ingestion in the fasting state, LT4 absorption rapidly increases and reaches a maximum at 1.5 to 2 hours.

    “After ingestion in the fasting state, absorption rapidly increases and reaches a maximum at 1.5 to 2 hours (19).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [19] Hays, 1991, Localization of human thyroxine absorption, Thyroid source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    An intact and normal intestinal mucosal epithelium is required for the absorption of drugs.

    “An intact and normal intestinal mucosal epithelium is required for the absorption of drugs.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    Endogenous and exogenous T4 cannot be distinguished by the human body and are handled equally.

    “Endogenous and exogenous T4 cannot be distinguished by the human body and are handled equally.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    In the small intestine, a large portion of LT4 is bound to intraluminal proteins.

    “In the small intestine, a large portion of LT4 is bound to intraluminal proteins.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    Thyroid homeostasis is regulated by classic hypothalamic-pituitary-thyroid negative feedback.

    “Thyroid homeostasis is regulated by classic hypothalamic–pituitary–thyroid negative feedback.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Premisenone given

    In the past 15 years, novel formulations (liquid solutions and soft gel capsules) have been introduced to the market and have shown superior efficacy.

    “In the past 15 years, novel formulations (liquid solutions and soft gel capsules) have been introduced to the market and have shown superior efficacy.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisenone given

    The intraluminal digestion of LT4 tablets comprises disintegration and dissolution in the stomach and absorption mainly in the small intestine.

    “The intraluminal digestion of LT4 tablets comprises disintegration and dissolution in the stomach and absorption mainly in the small intestine (Fig. 1).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    Weekly intramuscular (IM) and subcutaneous (SC) injection represent new methods for sustained drug delivery.

    “Weekly intramuscular (IM) and subcutaneous (SC) injection represent new methods for sustained drug delivery.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationcitation

    Novel formulations, such as liquid solutions and soft gel capsules, do not require dissolution, and are thus more efficient for hypothyroidism therapy.

    “Novel formulations, such as liquid solutions and soft gel capsules, do not require dissolution, and are thus more efficient for hypothyroidism therapy (16).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [16] Pabla, 2009, A comparative pH-dissolution profile study of selected commercial levothyroxine products using inductively coupled plasma mass spectrometry, Eur J Pharm Biopharm source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    LT4 can be rectally administered to patients who have difficulty swallowing.

    “LT4 can be rectally administered to patients who have difficulty swallowing.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Premisenone given

    The majority of patients can achieve biological euthyroidism with oral LT4 supplements.

    “The majority of patients can achieve biological euthyroidism with oral LT4 supplements.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisereasoning

    TSH released by the pituitary gland is a highly sensitive indicator for monitoring thyroid function.

    “TSH released by the pituitary gland is a highly sensitive indicator for monitoring thyroid function.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Generic and brand name LT4 tablets exhibit different dissolution-pH profiles, suggesting that excipients and manufacturing techniques influence tablet dissolution.

    “Notably, generic and brand name tablets exhibit different dissolution–pH profiles, suggesting that excipients and manufacturing techniques influence tablet dissolution (14).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [14] Virili, 2019, Gastrointestinal malabsorption of thyroxine, Endocr Rev source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Gastroparesis may delay stomach emptying and enable residual food to adsorb more oral LT4.

    “Gastroparesis may delay stomach emptying and enable residual food to adsorb more oral LT4 (48).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [48] Khraisha, 2015, Gastroparesis—a novel cause of persistent thyroid stimulating hormone elevation in hypothyroidism, J Louisiana State Med Soc

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Cystic fibrosis was reported to impair LT4 absorption in 1 patient.

    “Cystic fibrosis was reported to impair LT4 absorption in 1 patient (60).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [60] Giuffrida, 2020, Cystic fibrosis as a cause of malabsorption and increased requirement of levothyroxine, Thyroid source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    In the physiological state, the normal ratio of T4:T3 released by the thyroid is approximately 14:1.

    “Of note, in the physiological state, the normal ratio of T4:T3 released by the thyroid is approximately 14:1 (39).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [39] Wartofsky, 2013, Combination L-T3 and L-T4 therapy for hypothyroidism, Curr Opin Endocrinol Diabetes Obes source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    The deiodination of T4 produces both T3 and reverse T3 (rT3); T3 is the biologically active form and is approximately 5 times more potent than T4, while rT3 has little effect on the human body compared with T3.

    “The deiodination of T4 produces both T3 and reverse T3 (rT3). The difference between the 2 products is the site of deiodination (the removal of iodine from carbon 5 of the outer ring of T4 by deiodinase type 1 or 2, or the inner ring by deiodinase type 3) (38). T3 is the biologically active form and is approximately 5 times more potent than T4. rT3 has little effect on the human body compared with”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [38] Mol, 1985, Rapid and selective inner ring deiodination of thyroxine sulfate by rat-liver deiodinase, Endocrinology source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    The mean half-life (T1/2) is 7.5 days for T4 and 1.4 days for T3.

    “The mean half-life (T1/2) is 7.5 days for T4 and 1.4 days for T3 (40, 41).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [40] Gietka-Czernel, 2020, Expert opinion on liquid L-thyroxine usage in hypothyroid patients and new liquid thyroxine formulation—Tirosint SOL, Endokrynol Pol source

      Not checked in the free run.

    • cites [41] Gottwald-Hostalek, 2021, Triiodothyronine alongside levothyroxine in the management of hypothyroidism?, Curr Med Res Opin source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Since ∼70% of oral LT4 is absorbed in the duodenum, jejunum, and ileum, jejunostomy and bowel resection lead to a substantial decrease in drug absorption.

    “Since ∼70% of oral LT4 is absorbed in the duodenum, jejunum, and ileum, jejunostomy and bowel resection lead to a substantial decrease in drug absorption (52).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [52] Smyrniotis, 2000, Severe hypothyroidism in patients dependent on prolonged thyroxine infusion through a jejunostomy, Clin Nutr source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisenone given

    Four-fifths of circulating T3 are derived from the mono-deiodination of T4, while the remaining 20% is released directly from the thyroid.

    “Four-fifths of circulating T3 are derived from the mono-deiodination of T4, while the remaining 20% is released directly from the thyroid.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    A lactose-free formulation or gluten-free diet can rid patients with lactose intolerance or celiac disease of impaired absorption.

    “A lactose-free formulation or gluten-free diet can rid patients with lactose intolerance or celiac disease of impaired absorption, respectively (14, 64).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [14] Virili, 2019, Gastrointestinal malabsorption of thyroxine, Endocr Rev source

      Not checked in the free run.

    • cites [64] Collins, 2012, Celiac disease and hypothyroidism, Am J Med source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Intestinal lymphangiectasia and ulcerative colitis have been revealed to cause impaired LT4 absorption, although the underlying mechanisms remain unclear.

    “Some other intestinal dysfunctions, such as intestinal lymphangiectasia and ulcerative colitis, have been revealed to cause impaired LT4 absorption, although the underlying mechanisms remain unclear (58, 59).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [58] Menendez, 2021, Case report: use of biweekly intramuscular levothyroxine therapy in a pediatric patient with acquired hypothyroidism and malabsorption from intestinal lymphangiectasia, Horm Res Paediatr

      Not checked in the free run.

    • cites [59] Virili, 2019, Ulcerative colitis as a novel cause of increased need for levothyroxine, Front Endocrinol (Lausanne) source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    Impaired bioavailability of LT4 is a common cause of off-target serum TH levels and has been reported in patients with many medical conditions, including concurrent diseases, coingestion with drugs or food, a switch in the LT4 preparation, improper storage, or poor compliance.

    “Impaired bioavailability of LT4 is a common cause of off-target serum TH levels and has been reported in patients with many medical conditions, including concurrent diseases, coingestion with drugs or food, a switch in the LT4 preparation, improper storage, or poor compliance.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    The common downstream catabolites of LT4 are diiodotyrosine and monoiodotyrosine.

    “The common downstream catabolites are diiodotyrosine and monoiodotyrosine.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Critically ill patients may exhibit reduced intestinal absorption of LT4 and increased conversion of T4 to rT3, regardless of the causes of the critical illness.

    “Notably, critically ill patients may exhibit reduced intestinal absorption of LT4 and increased conversion of T4 to rT3, regardless of the causes of the critical illness (57).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [57] Imberti, 2010, Increased levothyroxine requirements in critically ill patients with hypothyroidism, Minerva Anestesiol

      Not checked in the free run.

  • May combine two claims.

    Premisereasoning

    Patients with impaired LT4 bioavailability will present with elevated TSH levels and reduced T3 and T4 levels and thus require a dose adjustment (>1.9 μg/kg).

    “Patients will present with elevated TSH levels, and reduced T3 and T4 levels and thus require a dose adjustment (>1.9 µg/kg).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    The 2 major metabolic routes of LT4 are deiodination and conjugation.

    “The 2 major metabolic routes of LT4 are deiodination and conjugation.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    A rare case of TH malabsorption was reported to be induced by congestive heart failure, which may cause intestinal dysfunction and chronic passive congestion of the liver.

    “In addition, a rare case of TH malabsorption was reported to be induced by congestive heart failure, which may cause intestinal dysfunction and chronic passive congestion of the liver (63).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [63] Surks, 1973, Determination of iodothyronine absorption and conversion of L-thyroxine (T4) to L-triiodothyronine (T3) using turnover rate techniques, J Clin Invest source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In patients with nephrotic syndrome, T4-bound albumin and free T4 (FT4) are excreted into the urine, and TSH levels are elevated despite a dose increase.

    “In patients with nephrotic syndrome, T4-bound albumin and free T4 (FT4) are excreted into the urine, and TSH levels are elevated despite a dose increase (35, 36).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [35] Benvenga, 2015, Do not forget nephrotic syndrome as a cause of increased requirement of levothyroxine replacement therapy, Eur Thyroid J source

      Not checked in the free run.

    • cites [36] Iqbal, 2022, It's not lupus this time! A case of worsening hypothyroidism in a patient with nephrotic syndrome, Cureus J Med Sci

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Lactose intolerance and celiac disease are among the most frequent intestinal diseases responsible for malabsorption and may both impair intestinal absorption of drugs and nutrients via hydrolysis and complexation.

    “In addition to surgery, lactose intolerance and celiac disease are among the most frequent intestinal diseases responsible for malabsorption. They may both impair intestinal absorption of drugs and nutrients via hydrolysis and complexation (25, 26, 55).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [25] Asik, 2014, Decrease in TSH levels after lactose restriction in Hashimoto's thyroiditis patients with lactose intolerance, Endocrine source

      Not checked in the free run.

    • cites [26] Cellini, 2014, Systematic appraisal of lactose intolerance as cause of increased need for oral thyroxine, J Clin Endocrinol Metab source

      Not checked in the free run.

    • cites [55] Munoz-Torres, 2006, Lactose intolerance revealed by severe resistance to treatment with levothyroxine, Thyroid source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Drugs may cause the malabsorption of LT4 via reduced gastric dissolution due to alkalization; gastric pH is impaired by PPIs, H2 antagonists, or other antacids.

    “Drugs may cause the malabsorption of LT4 via reduced gastric dissolution due to alkalization. Gastric pH is impaired by PPIs, H2 antagonists, or other antacids (11, 79).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [11] Yue, 2015, When bioequivalence in healthy volunteers may not translate to bioequivalence in patients: differential effects of increased gastric pH on the pharmacokinetics of levothyroxine capsules and tablets, J Pharm Pharm Sci source

      Not checked in the free run.

    • cites [79] Jonderko, 1992, Effect of cimetidine and ranitidine on absorption of [125I]levothyroxine administered orally, Acta Pharmacol Sin

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Biological hypothyroidism is easily corrected a few days after withdrawal of drugs reducing intestinal absorption, while a longer time (weeks to months) is needed for drugs affecting in vivo metabolism.

    “Biological hypothyroidism is easily corrected a few days after withdrawal of drugs reducing intestinal absorption, while a longer time (weeks to months) is needed for drugs affecting in vivo metabolism (87, 94).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [87] Guarda, 2019, Mifepristone increases thyroid hormone requirements in patients with central hypothyroidism: a multicenter study, J Endocr Soc source

      Not checked in the free run.

    • cites [94] Csako, 2001, Exaggerated levothyroxine malabsorption due to calcium carbonate supplementation in gastrointestinal disorders, Ann Pharmacother source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Ranitidine had no effect on T3, T4, and TSH levels, whereas cimetidine reduced the AUC of LT4 by more than 20% compared with the placebo.

    “Ranitidine, for instance, had no effect on T3, T4, and TSH levels, whereas cimetidine reduced the AUC of LT4 by more than 20% compared with the placebo (79).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [79] Jonderko, 1992, Effect of cimetidine and ranitidine on absorption of [125I]levothyroxine administered orally, Acta Pharmacol Sin

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Liquid formulations are spared from gastric dissolution and are mixed more evenly than solid formulations.

    “Liquid formulations are spared from gastric dissolution and are mixed more evenly than solid formulations.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Premisenone given

    The majority of patients with coingestion are asymptomatic and receive constant doses of LT4.

    “The majority of patients with coingestion are asymptomatic and receive constant doses of LT4.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    The results for H2 antagonists are conflicting, partially due to their more moderate and slower effects on H+ secretion than those of PPIs.

    “The results for H2 antagonists are conflicting (79), partially due to their more moderate and slower effects on H+ secretion than those of PPIs.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [79] Jonderko, 1992, Effect of cimetidine and ranitidine on absorption of [125I]levothyroxine administered orally, Acta Pharmacol Sin

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Metformin suppresses TSH levels.

    “Interestingly, metformin suppresses TSH levels (92, 93).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [92] Al-Alusi, 2015, Metformin does not suppress serum thyrotropin by increasing levothyroxine absorption, Thyroid source

      Not checked in the free run.

    • cites [93] Isidro, 2007, Metformin reduces thyrotropin levels in obese, diabetic women with primary hypothyroidism on thyroxine replacement therapy, Endocrine source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Interpretationcitation

    The potential mechanism by which metformin suppresses TSH may be enhancing the inhibitory modulatory effect of THs on central TSH secretion and changing the affinity and/or the number of TH receptors.

    “The potential mechanism may be enhancing the inhibitory modulatory effect of THs on central TSH secretion and changing the affinity and/or the number of TH receptors.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Phenytoin and imatinib inactivate LT4 via nondeiodinative hepatic metabolism and decrease the ratio of T3 to T4.

    “Similarly, phenytoin and imatinib inactivate LT4 via nondeiodinative hepatic metabolism and decrease the ratio of T3 to T4 (89, 90).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [89] de Groot, 2005, Imatinib induces hypothyroidism in patients receiving levothyroxinc, Clin Pharmacol Ther source

      Not checked in the free run.

    • cites [90] Faber, 1985, The effects of phenytoin (diphenylhydantoin) on the extrathyroidal turnover of thyroxine, 3,5,3′-triiodothyronine, 3,3′,5′-triiodothyronine, and 3′,5′-diiodothyronine in man, J Clin Endocrinol Metab source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Estrogen can increase TBG and albumin concentrations and decrease FT4 levels, whereas androgen has the opposite effects.

    “Estrogen can increase TBG and albumin concentrations and decrease FT4 levels, whereas androgen has the opposite effects (34, 91).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [34] Arafah, 2001, Increased need for thyroxine in women with hypothyroidism during estrogen therapy, N Engl J Med source

      Not checked in the free run.

    • cites [91] Arafah, 1994, Decreased levothyroxine requirement in women with hypothyroidism during androgen therapy for breast cancer, Ann Intern Med source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    Severe refractory hypothyroidism is not common in patients with concomitant disease or conditions.

    “Furthermore, clinicians should be aware that severe refractory hypothyroidism is not common in patients with concomitant disease or conditions.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    The increase in FT4 levels compared with baseline also indicates absorption ability, although the threshold value ranges from 50% to 250% in different studies.

    “The increase in FT4 levels compared with baseline also indicates the absorption ability, although the threshold value ranges from 50% to 250% in different studies (132, 133).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [132] Simsir, 2019, Levothyroxine absorption test results in patients with TSH elevation resistant to treatment, Endocrine source

      Not checked in the free run.

    • cites [133] Elbasan, 2020, Refractory hypothyroidism to levothyroxine treatment: five cases of pseudomalabsorption, Acta Endocrinol (Buchar) source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Dosing before dinner slightly reduces the therapeutic efficacy of LT4, since 2 to 4 hours are usually required for the stomach to empty.

    “Dosing before dinner slightly reduces the therapeutic efficacy of LT4 (103), since 2 to 4 hours are usually required for the stomach to empty.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [103] Ala, 2015, Dose administration time from before breakfast to before dinner affect thyroid hormone levels?, Caspian J Intern Med

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A number of studies have evaluated the interchangeability of LT4 among manufacturers, brands, or batches, and the results are controversial.

    “A number of studies have evaluated the interchangeability of LT4 among manufacturers, brands, or batches (106–108), and the results are controversial.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [106] Gottwald-Hostalek, 2017, New levothyroxine formulation meeting 95-105% specification over the whole shelf-life: results from two pharmacokinetic trials, Curr Med Res Opin source

      Not checked in the free run.

    • cites [107] Lipp, 2019, A new formulation of levothyroxine engineered to meet new specification standards, Curr Med Res Opin source

      Not checked in the free run.

    • cites [108] Eisenberg, 2009, TSH-based protocol, tablet instability, and absorption effects on L-T-4 bioequivalence, Thyroid source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationreasoning

    This phenomenon might be explained by different pharmacokinetic properties due to excipients and manufacturing techniques.

    “This phenomenon might be explained by different pharmacokinetic properties due to excipients and manufacturing techniques.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    As reported in US studies, 20% of patients switch to another LT4 generic preparation at least once within the first year of initiating therapy, and a change in the LT4 preparation is the leading cause (56.0%) of the TH level fluctuation observed in LT4-treated patients.

    “As reported in US studies, 20% of patients switch to another LT4 generic preparation at least once within the first year of initiating therapy, and a change in the LT4 preparation is the leading cause (56.0%) of the TH level fluctuation observed in LT4-treated patients (118, 119).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [118] Hennessey, 2010, Adverse event reporting in patients treated with levothyroxine: results of the pharmacovigilance task force survey of the American Thyroid Association, American Association of Clinical Endocrinologists, and the Endocrine Society, Endocr Pract source

      Not checked in the free run.

    • cites [119] Brito, 2022, Rates of, and factors associated with, switching among generic levothyroxine preparations in commercially insured American adults, Endocrine source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In 5 patients evaluated with the LT4 absorption protocol, 2 had impaired absorption (<60%) with the underlying cause revealed in subsequent examinations, and the remaining 3 were diagnosed with pseudomalabsorption.

    “Simsir and colleagues used the protocol to evaluate the absorption ability in 5 patients (132). Two patients had impaired absorption (<60%) and the underlying cause was revealed in subsequent examinations. The remaining 3 individuals were diagnosed with pseudomalabsorption.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [132] Simsir, 2019, Levothyroxine absorption test results in patients with TSH elevation resistant to treatment, Endocrine source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Changed formulations are sometimes related to altered bioavailability, although bioequivalence between old and new formulations has been confirmed with Food and Drug Administration-approved protocol.

    “The changed formulations are sometimes related to altered bioavailability, although bioequivalence between old and new formulations has been confirmed with Food and Drug Administration–approved protocol (115).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [115] Olveira, 1997, Altered bioavailability due to changes in the formulation of a commercial preparation of levothyroxine in patients with differentiated thyroid carcinoma, Clin Endocrinol (Oxf) source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Social factors associated with poor compliance include older age, irregular medical visits, poor knowledge about medications, lack of assistance when taking medication, affordability, a busy schedule, and discontinuation of medications when symptomatic relief occurs.

    “The main social factors associated with poor compliance are older age, irregular medical visits, poor knowledge about medications, lack of assistance when taking medication, affordability, a busy schedule, and the discontinuation of medications when symptomatic relief occurs (10).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [10] Kumar, 2019, Adherence to levothyroxine tablet in patients with hypothyroidism, Cureus

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Acid excipients, such as lactose, mannitol, and sorbitol, can induce drug instability in tablets, while basic excipients can be added to improve the stability of LT4 tablets.

    “Acid excipients, such as lactose, mannitol, and sorbitol, can induce drug instability in tablets (112, 113), while basic excipients can be added to improve the stability of LT4 tablets (114).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [112] Kaur, 2021, Investigating the influence of excipients on the stability of levothyroxine sodium pentahydrate, Mol Pharm source

      Not checked in the free run.

    • cites [113] Ledeti, 2020, Stability and compatibility studies of levothyroxine sodium in solid binary systems-instrumental screening, Pharmaceutics source

      Not checked in the free run.

    • cites [114] Patel, 2003, The effect of excipients on the stability of levothyroxine sodium pentahydrate tablets, Int J Pharm source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In the same study, 27.3% of patients had low adherence to LT4, denoting frequent drug omissions.

    “Even worse, 27.3% of patients had low adherence to LT4, denoting “frequent” drug omissions.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [10] Kumar, 2019, Adherence to levothyroxine tablet in patients with hypothyroidism, Cureus

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In a 2010 randomized, double-blind, crossover trial recruiting 90 patients, reduced TSH levels and elevated total T3 and total T4 (TT4) levels were observed in patients taking LT4 at bedtime, with no significant difference in quality of life or preference.

    “In 2010, a randomized, double-blind, crossover trial recruiting 90 patients examined the efficacy of taking LT4 at bedtime (104). Reduced TSH levels and elevated total T3 and total T4 (TT4) levels were observed in patients taking LT4 at bedtime, with no significant difference in quality of life or preference.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [104] Bolk, 2010, Effects of evening vs morning levothyroxine intake a randomized double-blind crossover trial, Arch Intern Med source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Drug-related factors contributing to poor compliance include coadministration of multiple drugs, administration more than once daily, and fasting condition administration.

    “The coadministration of multiple drugs, administration >1/day, and fasting condition administration were revealed to be drug-related factors contributing to poor compliance (127).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [127] Bezerra, 2021, Polypharmacy simulation and pharmacotherapy perceptions among students from a university in Ceará: a pilot study.] Simulação de polimedicação e percepções sobre farmacoterapia em estudantes de universidade no Ceará: estudo-piloto, Rev Bras Educ Méd

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The types of substrate potentially influence the degradation rate of drugs.

    “Notably, the types of substrate potentially influence the degradation rate of drugs (157).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [157] Vakili, 2017, Application of a handheld NIR spectrometer in prediction of drug content in inkjet printed orodispersible formulations containing prednisolone and levothyroxine, Int J Pharm source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    Many conditions can reduce the bioavailability of oral LT4 tablets.

    “However, as mentioned above, many conditions can reduce the bioavailability of oral LT4 tablets.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    T3 monotherapy failed to suppress TSH levels and patients presented with even more hyperthyroid symptoms, entailing closer monitoring.

    “T3 monotherapy failed to suppress TSH levels and patients presented with even more hyperthyroid symptoms, entailing closer monitoring.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [168] Jonklaas, 2016, Daily Administration of short-acting liothyronine is associated with significant triiodothyronine excursions and fails to alter thyroid-responsive parameters, Thyroid source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    LT4 salt rapidly replaced DTE and became the standard therapy for hypothyroidism because it had fewer adverse effects and more accurate dosing.

    “LT4 salt rapidly replaced DTE and became the standard therapy for hypothyroidism as there were fewer adverse effects and more accurate dosing (141).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [141] Virili, 2019, Novel thyroxine formulations: a further step toward precision medicine, Endocrine source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Previous combination of T3 and T4 added a certain dose of T3 tablets while reducing T4 administration proportionally, requiring patients to take more than 1 pill and/or split pills, which led to confusion and dose variation.

    “The previous combination of T3 and T4 added a certain dose of T3 tablets while reducing the T4 administration proportionally. Patients had to take more than 1 pill and/or split pills, which inevitably led to confusion and dose variation (156).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [156] Alomari, 2018, Printing T-3 and T-4 oral drug combinations as a novel strategy for hypothyroidism, Int J Pharm source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationcitation

    Considering that the physiological ratio of T3:T4 secreted by the thyroid gland is approximately 1:14 and the residual thyroid has secretory function, a ratio between 1:8 and 1:13 may be more appropriate.

    “Considering that the physiological ratio of T3:T4 secreted by the thyroid gland is approximately 1:14 and the residual thyroid has secretory function, a ratio between 1:8 and 1:13 may be more appropriate (154).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [154] DiStefano J, 2019, Predicting optimal combination LT4 + LT3 therapy for hypothyroidism based on residual thyroid function, Front Endocrinol (Lausanne) source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Taken together, liquid solutions have higher absorption, faster Tmax, and lower and more stable TSH levels than solid formulations, partially due to better intestinal absorption.

    “Taken together, these results show that liquid solutions have higher absorption, faster Tmax, and lower and more stable TSH levels than solid formulations, partially due to better intestinal absorption.”
    Quote in the paperSubstantial claim0 of 6 sources checked
    • cites [182] Ferrara, 2017, Treatment pattern and frequency of serum TSH measurement in users of different levothyroxine formulations: a population-based study during the years 2009-2015, Endocrine source

      Not checked in the free run.

    • cites [186] Yue, 2012, Pharmacokinetics and potential advantages of a new oral solution of levothyroxine vs. other available dosage forms, Arzneimittel-Forschung-Drug Res

      Not checked in the free run.

    • cites [187] Negro, 2014, Levothyroxine liquid solution versus tablet for replacement treatment in hypothyroid patients, Endocr Pract source

      Not checked in the free run.

    • cites [188] Cassio, 2013, Comparison between liquid and tablet formulations of levothyroxine in the initial treatment of congenital hypothyroidism, J Pediatr source

      Not checked in the free run.

    • cites [189] Peroni, 2014, Congenital hypothyroidism treatment in infants: a comparative study between liquid and tablet formulations of levothyroxine, Horm Res Paediatr source

      Not checked in the free run.

    • cites [190] Virili, 2018, Levothyroxine therapy: changes of TSH levels by switching patients from tablet to liquid formulation. a systematic review and meta-analysis, Front Endocrinol (Lausanne) source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In a phase I, double-blind RCT of 12 healthy volunteers, PZL showed a 1 hour later Tmax, an approximately 30% lower Cmax, and an approximately 6-hour T1/2, with hemodynamic and sleep parameters not significantly different between PZL and conventional T3 groups.

    “The researchers subsequently conducted a phase I, double-blind RCT of 12 healthy volunteers (180). Laboratory tests showed a release profile similar to the previous animal study: a 1 hour later Tmax, an ∼30% lower Cmax, and an ∼6-hour T1/2. The hemodynamic and sleep parameters were not significantly different between the PZL and conventional T3 groups.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [180] Dumitrescu, 2022, Extended absorption of liothyronine from poly-zinc-liothyronine: results from a phase 1, double-blind, randomized, and controlled study in humans, Thyroid source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    The proportion of patients taking liquid solutions is presumed to be lower in other European countries and North America than in Italy.

    “Considering that it was first introduced to the Italian market, the proportion of patients taking liquid solutions is presumed to be lower in other European countries and North America.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [182] Ferrara, 2017, Treatment pattern and frequency of serum TSH measurement in users of different levothyroxine formulations: a population-based study during the years 2009-2015, Endocrine source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In a 2019 phase II, open-label, uncontrolled, parallel trial in 36 thyroidectomized individuals, T3S plus T4 produced a decreased T4/T3 ratio with no reduction in T3 levels compared with LT4 monotherapy, and an increase in TSH levels.

    “In 2019, a phase II, open-label, uncontrolled, parallel trial investigating the efficacy and safety of T3S plus T4 was conducted in 36 thyroidectomized individuals (178). A decreased T4/T3 ratio with no reduction in T3 levels was observed compared with LT4 monotherapy. Interestingly, an increase in TSH levels was also observed, potentially due to a decrease in serum T4 levels.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [178] Santini, 2019, Treatment of hypothyroid patients with L-thyroxine (L-T4) plus triiodothyronine sulfate (T3S). A phase II, open-label, single center, parallel groups study on therapeutic efficacy and tolerability, Front Endocrinol (Lausanne) source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given

    Capsules prepared with hydrophilic swellable matrix may improve the release pattern.

    “Capsules prepared with hydrophilic swellable matrix may improve the release pattern.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisenone given

    In 2007, liquid LT4 stored in monodose vials (Tirosint SOL) was developed by IBSA and is available on the Italian market.

    “In 2007, liquid LT4 stored in monodose vials (Tirosint SOL) was developed by IBSA, an Italian–Swiss company, and is available on the Italian market.”
    Quote in the paperNot a substantial claim

  • The quote only partly states this claim.

    Premisecitation

    A novel platform consisting of solid rods prepared with a mixture of T3 and ethylene-vinyl acetate could release T3 in a relatively stable manner for over 6 months in rats and dogs.

    “In vivo experiments with rats and dogs showed that this platform could release T3 in a relatively stable manner for over 6 months.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [175] Idrees, 2019, Sustained release T3 therapy: animal models and translational applications, Front Endocrinol (Lausanne) source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    After oral administration, PZL can leak out from capsules and adhere to the mucosa of the gastrointestinal tract like a drug depot, and T3 is then released into the intestinal lumen and ultimately absorbed into the bloodstream.

    “After oral administration, PZL can leak out from capsules and adhere to the mucosa of the gastrointestinal tract like a “drug depot” (Fig. 6C). T3 is then released into the intestinal lumen and ultimately absorbed into the bloodstream.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [179] Da Conceicao, 2018, Metal coordinated poly-zinc-liothyronine provides stable circulating triiodothyronine levels in hypothyroid rats, Thyroid source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In a 2022 propensity-matched study involving 5342 patients in Korea, incidences of heart failure and stroke were increased in patients with a longer duration of LT3 use (heart failure incidence rate ratio = 1.664, P = .049; stroke incidence rate ratio = 1.757, P = .025).

    “In 2022, a propensity-matched study involving 5342 patients in Korea showed astonishing results (171). The incidences of heart failure and stroke were increased in patients with a longer duration of LT3 use (heart failure incidence rate ratio = 1.664, P = .049, stroke incidence rate ratio = 1.757, P = .025).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [171] Yi, 2022, Heart failure and stroke risks in users of liothyronine with or without levothyroxine compared with levothyroxine alone: a propensity score-matched analysis, Thyroid source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In 28 thyroidectomized patients administered T3S orally, serum T3S levels peaked 2 to 4 hours after administration and declined sharply in the next 10 hours, while T3 remained steady but increased in serum for more than 48 hours, with no adverse events observed.

    “Santini et al conducted a study among 28 thyroidectomized patients administered T3S orally (177). Although serum T3S levels peaked 2 to 4 hours after administration and declined sharply in the next 10 hours, the level of its desulfated (by liver) product, T3, remained steady but increased in serum for more than 48 hours. Even more surprisingly, no adverse events were observed.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [177] Santini, 2014, Steady-state serum T-3 concentrations for 48 hours following the oral administration of a single dose of 3,5,3′-triiodothyronine sulfate (T3S), Endocr Pract source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Da Conceicao and colleagues synthesized poly-zinc-liothyronine (PZL) and loaded it into gelatin capsules.

    “More recently, Da Conceicao and colleagues synthesized poly-zinc-liothyronine (PZL) and loaded it into gelatin capsules (179).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [179] Da Conceicao, 2018, Metal coordinated poly-zinc-liothyronine provides stable circulating triiodothyronine levels in hypothyroid rats, Thyroid source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    An animal study demonstrated that PZL capsules had an approximately 30% lower Cmax, an approximately 6 hour later time to peak serum concentration (Tmax), and a plateau time that was approximately 3 hours longer than conventional T3 capsules.

    “An animal study demonstrated an ∼30% lower Cmax, a ∼6 hour later time to peak serum concentration (Tmax), and a plateau time that was ∼3 hours longer than in conventional T3 capsules.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [179] Da Conceicao, 2018, Metal coordinated poly-zinc-liothyronine provides stable circulating triiodothyronine levels in hypothyroid rats, Thyroid source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    There are 2 metabolites from T3S: bioactive T3 via desulfation or bioinactive 3,3′-diiodothyronine sulfate generated by deiodinase type 1.

    “There are 2 metabolites from T3S: bioactive T3 via desulfation or bioinactive 3,3′-diiodothyronine sulfate generated by deiodinase type 1.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [176] Santini, 1996, Study of serum 3,5,3′-triiodothyronine sulfate concentration in patients with systemic non-thyroidal illness, Eur J Endocrinol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Liquid LT4 can be administered directly through feeding tubes in patients receiving enteral feeding, and is preferred by nurses due to convenience.

    “In addition, a liquid LT4 formulation can be administered directly through feeding tubes in patients receiving enteral feeding, and thus are preferred by nurses due to their convenience (193).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [193] Pirola, 2014, Comparison between liquid and tablet levothyroxine formulations in patients treated through enteral feeding tube, J Endocrinol Invest source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    Calcium and iron supplements are common concomitant drugs and can reduce the absorption of LT4 tablets through direct complexation.

    “As mentioned above, calcium and iron supplements are common concomitant drugs and can reduce the absorption of LT4 tablets through direct complexation.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Oral administration of a solution via a feeding tube is a preferred option for patients with myxedema coma when IV LT4 is unavailable.

    “The oral administration of a solution via a feeding tube is also a preferred option for patients with myxedema coma when IV LT4 is unavailable (194).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [194] Rajendran, 2021, Oral levothyroxine is an effective option for myxedema coma: a single-centre experience, Eur Thyroid J

      Not checked in the free run.

  • May combine two claims.

    Study design and conductreasoning

    The levels of evidence were generally low and there was a high risk of reporting bias.

    “The levels of evidence were generally low and, obviously, there was a high risk of reporting bias.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    In a 2016 randomized, double-blind, placebo-controlled, crossover trial, 77 patients completed the study at 12 weeks, and no significant differences were observed in FT3, FT4, or TSH, indicating that liquid LT4 can eliminate malabsorption due to coingestion with breakfast.

    “Seventy-seven patients completed the study at 12 weeks. No significant differences were observed in FT3, FT4, or TSH, indicating that liquid LT4 can eliminate malabsorption due to coingestion with breakfast.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [98] Cappelli, 2016, A double-blind placebo-controlled trial of liquid thyroxine ingested at breakfast: results of the TICO study, Thyroid source

      Not checked in the free run.

  • May combine two claims.

    Study design and conductown data

    Among the 31 included articles investigating LT4 formulations, 14 were case reports or case series, 5 were retrospective cohort studies, 2 were prospective cohort studies, and 8 were prospective pre-post self-control studies.

    “Among the 31 included articles investigating LT4 formulations, 14 were case reports or case series, 5 were retrospective cohort studies, 2 were prospective cohort studies, and 8 were prospective pre–post self-control studies.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    A retrospective cohort study in 31 pregnant patients with hypothyroidism showed a decreased daily LT4 dose in 14 patients taking liquid solutions and 17 taking tablets, with no significant difference in age, weight, or TH levels.

    “A retrospective cohort study by Cappelli et al in 31 pregnant patients with hypothyroidism showed a decreased daily LT4 dose in 14 patients taking liquid solutions and 17 taking tablets, with no significant difference in age, weight, or TH levels (200).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [200] Cappelli, 2016, Levothyroxine liquid solution versus tablet form for replacement treatment in pregnant women, Gynecol Endocrinol source

      Not checked in the free run.

    • The authors state this as an assumption: Pregnancy has little effect on the malabsorption of LT4 but impairs bioavailability via estrogen-induced TBG elevations.

  • May combine two claims.

    Study design and conductreasoning

    Common weak points in settings included a lack of washout periods, nonstandardized interventions, recruitment of patients with different hypothyroidism etiologies and target TH ranges, selective outcome reporting, and unavailability of long-term effects.

    “Common weak points in settings included a lack of washout periods, nonstandardized interventions, recruitment of patients with different hypothyroidism etiologies and target TH ranges, selective outcome reporting (TSH, FT3, FT4, or LT4 dose), and unavailability of long-term effects, etc.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    In a 2021 randomized, crossover study including 50 patients, the FT4 level was somewhat lower in the solution group than in the tablet group (1.448 ± 0.232 vs 1.363 ± 0.216 ng/dL, P = .008), and the TSH level was slightly higher in the solution group.

    “In 2021, however, a randomized, crossover study by Markantes et al including 50 patients found that the FT4 level was somewhat lower in the solution group than in the tablet group (1.448 ± 0.232 vs 1.363 ± 0.216 ng/dL, P = .008) (191). The TSH level was also slightly higher in the solution group than in the tablet group.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [191] Markantes, 2021, Therapeutic equivalence of a new preparation of liquid levothyroxine with tablets in patients with overt primary hypothyroidism, Eur Thyroid J

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In a randomized, 2-arm, crossover trial in euthyroid volunteers with a washout period of 45 days, IV esomeprazole reduced the AUC of tablets, while the AUC of the capsules was not altered by esomeprazole.

    “Yue et al conducted a randomized, 2-arm, crossover trial in euthyroid volunteers with a washout period of 45 days (11). Thirty-two individuals were recruited in the LT4 absorption test. In line with previous studies, IV esomeprazole reduced the AUC of tablets. The AUC of the capsules was not altered by esomeprazole.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [11] Yue, 2015, When bioequivalence in healthy volunteers may not translate to bioequivalence in patients: differential effects of increased gastric pH on the pharmacokinetics of levothyroxine capsules and tablets, J Pharm Pharm Sci source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A meta-analysis by Laurent et al based on 8 prospective or randomized controlled studies found reduced TSH levels in patients with malabsorption who were taking liquid formulations, but TSH levels did not differ significantly between tablets and liquid preparations in the nonmalabsorption group.

    “As revealed by a meta-analysis by Laurent et al (219) based on 8 prospective or randomized controlled studies, reduced TSH levels were observed in patients with malabsorption who were taking liquid formulations. However, TSH levels did not differ significantly between tablets and liquid preparations in the nonmalabsorption group.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [219] Laurent, 2018, Liquid L-thyroxine versus tablet L-thyroxine in patients on L- thyroxine replacement or suppressive therapy: a meta-analysis, Endocrine source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Some patients may squeeze the liquid LT4 ampoule directly into their mouth for convenience, which may cause buccal absorption and poor efficacy.

    “Some patients may simply squeeze the liquid LT4 ampoule directly into their mouth for convenience, which may cause buccal absorption and poor efficacy (217).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [217] Benvenga, 2017, Intestinal absorption and buccal absorption of liquid levothyroxine, Endocrine source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Patients taking soft gel capsules experienced fewer dose adjustments and improved symptoms than patients taking tablets.

    “Patients taking soft gel capsules experienced fewer dose adjustments and improved symptoms than patients taking tablets (229).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [229] Ernst, 2017, Retrospective study of patients switched from tablet formulations to a gel cap formulation of levothyroxine: results of the control switch study, Drugs R D source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Malabsorption due to calcium supplements, PPIs, breakfast, H. pylori infection, and gastroparesis was eradicated after switching from tablets to capsules.

    “Malabsorption due to calcium supplements (99), PPIs (226), breakfast (206), H. pylori infection (227), and gastroparesis (202) was eradicated after switching from tablets to capsules.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [99] Morini, 2019, In thyroxine-replaced hypothyroid postmenopausal women under simultaneous calcium supplementation, switch to oral liquid or softgel capsule l-thyroxine ensures lower serum TSH levels and favorable effects on blood pressure, total cholesterolemia and glycemia, Endocrine source

      Not checked in the free run.

    • cites [226] Vita, 2014, Tablet levothyroxine (L-T4) malabsorption induced by proton pump inhibitor: a problem that was solved by switching to L-T4 in soft gel capsule, Endocr Pract source

      Not checked in the free run.

    • cites [206] Cappelli, 2016, Thyroid hormone profile in patients ingesting soft gel capsule or liquid levothyroxine formulations with breakfast, Int J Endocrinol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The liquid preparation could ameliorate altered mood states, self-perception of mental well-being, and the TH profile in thyroidectomized patients.

    “Interestingly, the liquid preparation could ameliorate altered mood states, self-perception of mental well-being, and the TH profile in thyroidectomized patients (214), although the improvement in mood states may not have been attributable to improved thyroid functions but something else.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [214] Lombardi, 2017, Comparative study between the effects of replacement therapy with liquid and tablet formulations of levothyroxine on mood states, self-perceived psychological well-being and thyroid hormone profile in recently thyroidectomized patients, Endocrine source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Colucci et al conducted a clinical trial in 24 healthy volunteers according to the FDA-approved pharmacokinetic protocol for bioequivalence, and confirmed pharmacokinetic equivalence between LT4 soft gel capsules and tablets.

    “Colucci et al conducted a clinical trial in 24 healthy volunteers according to the Food and Drug Administration–approved pharmacokinetic protocol for bioequivalence. The study confirmed the pharmacokinetic equivalence between LT4 soft gel capsules and tablets (221).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [221] Colucci, 2011, Pharmacokinetic equivalence of a levothyroxine sodium soft capsule manufactured using the New Food and Drug Administration potency guidelines in healthy volunteers under fasting conditions, Ther Drug Monit source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    An in vitro study revealed that the dissolution time of soft gel capsules was approximately 20 minutes regardless of pH, which explains the discrepancy in AUCs in the trial.

    “An in vitro study revealed that the dissolution time of soft gel capsules was ∼20 minutes regardless of pH (228), which explains the discrepancy in AUCs in the trial.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [228] Fiorini, 2016, In vivo dissolution of levothyroxine soft gel capsules, Intern Emerg Med source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Genetic mutations of thyroid-specific proteins play a role in the development of fetal goiters.

    “Genetic mutations of thyroid-specific proteins also play a role in the development of fetal goiters (249–251).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [249] Caron, 2003, Compound heterozygous mutations in the thyroglobulin gene (1143delC and 6725G3 -&gt; A R2223H) resulting in fetal goitrous hypothyroidism, J Clin Endocrinol Metab source

      Not checked in the free run.

    • cites [250] Ghazi, 2005, Intrauterine diagnosis and management of fetal goitrous hypothyroidism: a report of an Iranian family with three consecutive pregnancies complicated by fetal Goiter, Thyroid source

      Not checked in the free run.

    • cites [251] Stoupa, 2020, First case of fetal goitrous hypothyroidism due to SLC5A5/NIS mutations, Eur J Endocrinol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    LT4 IV injection can augment the calorigenic effect of norepinephrine within minutes and thus exerts direct, rapid effects on the myocardium, which may lead to cardiac arrest.

    “LT4 IV injection can augment the calorigenic effect of norepinephrine within minutes and thus exerts direct, rapid effects on the myocardium, which may lead to cardiac arrest (238).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [238] Bacci, 1981, Cardiac-arrest after intravenous administration of levothyroxine, JAMA source

      Not checked in the free run.

  • May combine two claims.

    Premisereasoning

    The IM dosage can be administered once a week or split into 2 doses per week.

    “The dosage can be administered once a week or split into 2 doses per week.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    LT4 suppository content was uniform and stable over 90 days.

    “Hamada et al demonstrated that although LT4 suppository content was uniform and stable over 90 days, its release rate correlated directly with rectal pH (259).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [259] Hamada, 2015, Pharmaceutical studies of levothyroxine sodium hydrate suppository provided as a hospital preparation, Biol Pharm Bull source

      Not checked in the free run.

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    A 3- to 5-day course of IV LT4 with subsequent oral tablets is recommended to prevent potential adverse events and to save costs.

    “A 3- to 5-day course of IV LT4 with subsequent oral tablets is recommended to prevent potential adverse events and to save costs (240, 241).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [240] Barlow, 2020, Economic evaluation of a pharmacist-led 5-day therapeutic hold of IV levothyroxine at an academic medical center, Hosp Pharm source

      Not checked in the free run.

    • cites [241] Marino, 2021, Intravenous levothyroxine stewardship program at a tertiary academic medical center, Am J Health Syst Pharm source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Addressing maternal diseases and LT4 replacement is necessary for preventing potential fetal tracheal compression or other developmental malformations.

    “Addressing maternal diseases and LT4 replacement is necessary for preventing potential fetal tracheal compression or other developmental malformations (253).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [253] Blidda, 2011, Graves' disease in two pregnancies complicated by fetal goitrous hypothyroidism: successful in utero treatment with levothyroxine, Thyroid source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A 240-minute in vitro experiment showed approximately 20% release of LT4 at pH 8.2 and undetectable release at pH <7.2.

    “A 240-minute in vitro experiment showed an ∼20% release at pH 8.2 and undetectable release at pH <7.2.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [259] Hamada, 2015, Pharmaceutical studies of levothyroxine sodium hydrate suppository provided as a hospital preparation, Biol Pharm Bull source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Fetal goiters are usually detected by ultrasound examinations or amniocentesis in the second or third trimesters.

    “The conditions are usually detected by ultrasound examinations or amniocentesis in the second or third trimesters (252).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [252] Machado, 2019, Graves' disease complicated by fetal goitrous hypothyroidism treated with intra-amniotic administration of levothyroxine, BMJ Case Rep source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Certain excipients of soft gel capsules can elicit oral mucositis.

    “Of note, certain excipients of soft gel capsules can elicit oral mucositis (231).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [231] Messina, 2018, Oral mucositis induced by treatment with soft gel formulation of levothyroxine, Endocrine source

      Not checked in the free run.

  • May combine two claims.

    Study design and conductcitation

    A novel feedback control system simulator developed by Eisenberg et al was quantified from pharmacokinetic and physiological human data and was validated against several independent clinical data sets.

    “In 2008, a novel feedback control system simulator was developed by Eisenberg et al (153). The model was quantified from pharmacokinetic and physiological human data and was validated against several independent clinical data sets.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [153] Eisenberg, 2008, Extensions, validation, and clinical applications of a feedback control system simulator of the hypothalamo-pituitary-thyroid axis, Thyroid source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In a 32-year-old female patient with elevated TSH (98.22 mIU/L), after poor adherence and malabsorption were excluded, treatment with 200 μg/day IM LT4 then weekly IM injection at 500 μg for >1 year relieved hypothyroid symptoms and returned thyroid function to a normal range.

    “Peynirci et al reported a 32-year-old female patient with elevated TSH (98.22 mIU/L) (243). Poor adherence and malabsorption were excluded by examinations and LT4 absorption tests. She was started with 200 µg/day IM LT4 and then switched to weekly IM injection at 500 µg. After the treatment for >1 year, her hypothyroid symptoms were relieved, and her thyroid function returned to a normal range.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [243] Peynirci, 2018, Is parenteral levothyroxine therapy safe in intractable hypothyroidism?, J Natl Med Assoc

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The American Thyroid Association recommends an IV LT4 dose of 75% of the oral dose.

    “Hence, the American Thyroid Association recommends an IV LT4 dose of 75% of the oral dose (44).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [44] Jonklaas, 2014, Guidelines for the treatment of hypothyroidism: prepared by the American thyroid association task force on thyroid hormone replacement, Thyroid source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Subcutaneous injection produces smaller fluctuations in TSH levels and slower release into the circulation than intramuscular injection.

    “SC injection produces smaller fluctuations in TSH levels and slower release into the circulation than IM injection (153).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [153] Eisenberg, 2008, Extensions, validation, and clinical applications of a feedback control system simulator of the hypothalamo-pituitary-thyroid axis, Thyroid source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Polyethylene glycol was incompatible with LT4 and caused significant drug degradation.

    “Frustratingly, it was incompatible with LT4 and caused significant drug degradation.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [272] Stewart, 2021, Poly(caprolactone)-based subcutaneous implant for sustained delivery of levothyroxine, Int J Pharm source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The porous silicon membrane height was approximately 2 μm and it bound LT4 through hydrogen bonding.

    “The height of the porous silicon membrane was ∼2 µm and it bound LT4 through hydrogen bonding.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [269] Kashanian, 2016, Controlled delivery of levothyroxine using porous silicon as a drug nanocontainer, Aust J Chem source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Padula et al. suggested that a microemulsion system could include LT4 in reverse micelles and reduce LT4 skin permeation to approximately 1% of that in dimethyl-β-cyclodextrin solution.

    “Padula et al suggested that a microemulsion system could include LT4 in reverse micelles and reduce LT4 skin permeation to ∼1% of that in dimethyl-β-cyclodextrin solution, which is widely used in creams (268).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [268] Padula, 2009, Innovative formulations for the delivery of levothyroxine to the skin, Int J Pharm source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The average release rate was 30 to 100 μg/day and was close to the oral dose of LT4.

    “The average release rate was 30 to 100 µg/day and was close to the oral dose of LT4 (44).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [44] Jonklaas, 2014, Guidelines for the treatment of hypothyroidism: prepared by the American thyroid association task force on thyroid hormone replacement, Thyroid source

      Not checked in the free run.

    • cites [272] Stewart, 2021, Poly(caprolactone)-based subcutaneous implant for sustained delivery of levothyroxine, Int J Pharm source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    LT4-loaded PEG stearate coated solid lipid nanoparticles remained stable in the gastric environment and showed a gradual release of drug up to 60 hours in vitro.

    “Although the particles remained stable in the gastric environment and showed a gradual release of drug up to 60 hours in vitro, there were some unneglectable flaws to address.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [275] Kashanian, 2014, PEG-stearate coated solid lipid nanoparticles as levothyroxine carriers for oral administration, J Nanopart Res source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Real-time polymerase chain reaction showed expression of sodium-dependent thyroid hormone transporters on the apical membrane of Calu-3 cells, which were significantly affected by pH and temperature.

    “Real-time polymerase chain reaction showed expression of sodium-dependent TH transporters on the apical membrane of Calu-3 cells, which were significantly affected by pH and temperature.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [263] Agu, 2016, Thyroid hormone (levothyroxine) replacement via the respiratory route by inhalation: in vitro exploratory studies, Expert Opin Drug Deliv source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Only 10% of LT4 applied to bare skin was transferred through the epidermis, whereas a greater portion of LT4 was degraded by type III deiodinase in the skin.

    “According to a previous study by Santini et al, only 10% of LT4 applied to bare skin was transferred through the epidermis, whereas a greater portion of LT4 was degraded by type III deiodinase in the skin (265).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [265] Santini, 2003, Role for inner ring deiodination preventing transcutaneous passage of thyroxine, J Clin Endocrinol Metab source

      Not checked in the free run.

  • May combine two claims.

    Interpretationnone given

    Liquid solutions and soft gel capsules can circumvent malabsorption due to other medications and diseases, and improve patient compliance.

    “These formulations can circumvent malabsorption due to other medications and diseases, and improve patient compliance.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    Liquid solutions can also be used in patients with difficulty in swallowing.

    “Liquid solutions can also be used in patients with difficulty in swallowing.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Some LT4 formulations (PCL and PZL) have exhibited a promising release profile and are proposed for in vivo studies or human studies.

    “Some of these formulations (PCL and PZL) have exhibited a promising release profile and are proposed for in vivo studies or human studies.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisereasoning

    The pharmacokinetic properties and biocompatibility of LT4 nanomaterials remained untested.

    “The pharmacokinetic properties and biocompatibility remained untested.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [179] Da Conceicao, 2018, Metal coordinated poly-zinc-liothyronine provides stable circulating triiodothyronine levels in hypothyroid rats, Thyroid source

      Not checked in the free run.

    • cites [180] Dumitrescu, 2022, Extended absorption of liothyronine from poly-zinc-liothyronine: results from a phase 1, double-blind, randomized, and controlled study in humans, Thyroid source

      Not checked in the free run.

    • cites [272] Stewart, 2021, Poly(caprolactone)-based subcutaneous implant for sustained delivery of levothyroxine, Int J Pharm source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    Most studies of LT4 solutions and capsules have intrinsic flaws in study designs.

    “However, the debate is still ongoing since most studies have intrinsic flaws in study designs.”
    Quote in the paperNot a substantial claim
135 of 135

  • The authors state this as an assumption.

    The persistent or recurrent hypothyroid symptoms in LT4-treated patients are attributed to a low level of circulating T3, which plays a superior role to T4 in the feedback of the hypothalamus–pituitary–thyroid axis.

    “This phenomenon is assumed to be attributed to a low level of circulating T3, which plays a superior role to T4 in the feedback of the hypothalamus–pituitary–thyroid axis (144).”

  • The authors state this as an assumption.

    Pregnancy has little effect on the malabsorption of LT4 but impairs bioavailability via estrogen-induced TBG elevations.

    “Pregnancy is assumed to have little effect on the malabsorption of LT4 but impairs bioavailability via estrogen-induced TBG elevations.”

  • The paper relies on this without support.

    Poor compliance in most patients, except those with specific conditions such as bedridden individuals needing assistance and people with psychiatric disorders, originates from forgetfulness.

    “Except for patients with specific conditions, such as bedridden individuals needing assistance and people with psychiatric disorders, poor compliance in most patients originates from so-called “human nature,” in other words, forgetfulness.”

  • The paper relies on this without support.

    Fetal goiters in the uterus are induced by maternal thyroid dysfunction of various causes, either secondary to antithyroid treatment for maternal hyperthyroidism or compensatory to maternal hypothyroidism.

    “Fetal goiters in the uterus are induced by maternal thyroid dysfunction of various causes (either secondary to antithyroid treatment for maternal hyperthyroidism, or compensatory to maternal hypothyroidism).”

  • The paper relies on this without support.

    Rectal administration can bypass the hepatic first-pass effect.

    “Interestingly, although rectal administration can bypass the hepatic first-pass effect, plasma TH levels are normalized only with an additional 100% of the dose or more (257, 258).”

  • The paper relies on this without support.

    LT4 suppositories are not available in most medical institutions.

    “Since LT4 suppositories are not available in most medical institutions, IV LT4 preparations or extemporary tablet-dissolved solutions can be alternatives.”

  • The paper relies on this without support.

    The sublingual and buccal mucosa are highly vascularized, hence drug degradation by intestinal enzymes can be avoided.

    “The sublingual and buccal mucosa are highly vascularized, hence drug degradation by intestinal enzymes can be avoided.”

  • The paper relies on this without support.

    The presence of ethanol in the solution favors the permeation of LT4 through mucosal epithelium.

    “The presence of ethanol in the solution favors the permeation of LT4 through mucosal epithelium.”

  • The paper relies on this without support.

    LT4 can be added to creams to reduce deposits of adipose tissue on the skin.

    “LT4 can be added to creams to reduce deposits of adipose tissue on the skin.”

  • The paper relies on this without support.

    The weight of the average human body is more than 300 times the weight of rats.

    “Considering that the obtained plasma concentration was >2000 times that required for healthy humans (274) and the weight of the average human body is >300 times the weight of rats, the size of implants providing a therapeutic LT4 dose can be reduced to 5 to 14 times that of the current implants.”

  • The paper relies on this without support.

    Chitosan has unique properties such as biocompatibility, biodegradability, safety, and mucoadhesivity.

    “Chitosan has been a hotspot in recent years due to its unique properties, such as biocompatibility, biodegradability, safety, and mucoadhesivity.”

  • The paper relies on this without support.

    PLGA and PEG are linked and form PLGA–PEG–PLGA triblock polymers, which are water insoluble and biocompatible.

    “Poly D, L-lactic-co-glycolic acid (PLGA) and PEG are linked and form PLGA–PEG–PLGA triblock polymers, which are water insoluble and biocompatible.”

  • The paper relies on this without support.

    Patients can easily perform subcutaneous injections themselves, similar to insulin injection.

    “Patients can easily perform the injections themselves, similar to insulin injection.”
13 of 13

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Implant size is described as both reduced and multiplied

    Minor

    The text says the therapeutic implant size can be reduced, but then specifies a size 5 to 14 times that of the current implants, which would be an increase.

1 of 1

Cites

Flagged first, then by citations

35 of the 307 references couldn’t be matched to a known paper.

Research works printed but not linked: 3

  1. Menendez, 2021, Case report: use of biweekly intramuscular levothyroxine therapy in a pediatric patient with acquired hypothyroidism and malabsorption from intestinal lymphangiectasia, Horm Res Paediatr, 94, 126
  2. Bezerra, 2021, Polypharmacy simulation and pharmacotherapy perceptions among students from a university in Ceará: a pilot study.] Simulação de polimedicação e percepções sobre farmacoterapia em estudantes de universidade no Ceará: estudo-piloto, Rev Bras Educ Méd, 45, e158
  3. Liu, Data from: Supplemental materials for the review “Levothyroxine: impaired bioavailability and novel drug delivery formulations”

Cited by

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Authors
Liu, H., Li, W., Zhang, W., Sun, S., & Chen, C.
Affiliations
  • Renmin Hospital of Wuhan University (CN)
  • Wuhan University (CN)
Corresponding author
  • Sun, Shengrong
  • Chen, Chuang
ORCID
Venue
Endocrine Reviews
Publisher
The Endocrine Society
Published
2022-11-22
Volume
44
Issue
3
Pages
393-416
ISSN
  • 0163-769X (ISSN-L)
  • 1945-7189
DOI
10.1210/endrev/bnac030
PMC
PMC10166268
OpenAlex
W4309654737
Semantic Scholar
eea5cd0af37527e535223e9e2c64b38058fde4cf
Cited by
63
References
307
Citations by year
2026: 14 · 2025: 30 · 2024: 14 · 2023: 5
FWCI
1.74
Type
journal article
Language
en
Open access
Licence
Locations
  • Endocrine Reviews (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
Funders
  • Beijing Xisike Clinical Oncology Research Foundation (Y-SY201901-0189)
  • Fundamental Research Funds
  • Central Universities (2042019kf0229, no. 2042021kf0073)
  • Science and Technology Major Project of Hubei Province
  • Next-Generation AI Technologies (2019AEA170)
Topics
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Disorders and Treatments
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmaceutical Science › Advanced Drug Delivery Systems
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmaceutical Science › Drug Solubulity and Delivery Systems
Keywords
levothyroxine, drug delivery formulation, bioavailability, drug interactions, soft gel capsules, liquid solutions, sublingual administration, transdermal drug delivery, suppositories, sustained drug release, nanoparticles, nanomaterials, dysphagia, thyroid emergencies, medication adherence
MeSH terms
Capsules, Humans, Hypothyroidism, Thyroxine

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