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
Open accessAbstract
PURPOSE: Clinical studies have suggested that proton pump inhibitors may decrease levothyroxine absorption and an in vitro study suggested that the effect of pH on dissolution may differ with formulation. To determine the impact of formulation on the pharmacokinetics of levothyroxine in altered gastric pH conditions, this study compared the pharmacokinetics of levothyroxine capsules and tablets, two formulations deemed bioequivalent in healthy volunteers under fasting conditions, when taken with or without esomeprazole. METHODS: Two clinical studies were conducted in healthy volunteers given single dose levothyroxine (600 mg) with a 45-day washout period. In Study 1 (parallel-design/two-way crossover), 16 subjects received either levothyroxine capsules or tablets, each group with or without prior administration of intravenous esomeprazole (maximum dose of 80 mg). In Study 2 (two-way crossover), 16 subjects received both capsules or tablets after intravenous esomeprazole. Blood samples were collected pre-dose and up to 24 hours post-dose. Baseline-adjusted pharmacokinetic parameters were calculated: Cmax (maximal concentration), Tmax (time to Cmax), AUC0-t (area under the concentration-time curve from 0 to the last detectable concentration), AUC0-6 and AUC0-12 (areas under the curve from 0 to 6 and 12 hours, respectively). Analyses of variance were conducted to compare ln-transformed Cmax and AUC. Non-parametric Tmax analyses were done. RESULTS: In Study 1, esomeprazole caused a greater decrease in overall levothyroxine exposure of tablets vs. capsules (13% vs 6% for Cmax, 18% vs. 14% for AUC(0-6), 17% vs. 5% for AUC(0-12) and 10% vs. 8% for AUC(0-t)). In Study 2 esomeprazole administration resulted in a 16% smaller levothyroxine exposure with tablets vs. capsules. No statistically significant differences in Tmax were found. CONCLUSIONS: Although both formulations are considered "bioequivalent" in healthy volunteers, they may not necessarily be bioequivalent in patients with impaired gastric pH conditions. Levothyroxine capsules may therefore be more appropriate for patients with decreased gastric acidity.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
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?
Chemical equivalence does not automatically correspond to bioequivalence, which is determined by pharmacokinetic tests on healthy volunteers but may differ from actual bioequivalence in patients in different clinical settings.
“However, it is known that chemical equivalence does not automatically correspond to bioequivalence, which is determined by pharmacokinetic tests on healthy volunteers (28) but may differ from actual bioequivalence in patients in different clinical settings (29).”
From ETA guidelines for the use of levothyroxine sodium preparations in monotherapy to optimize the treatment of hypothyroidism (2025) · cites this paper as [29]
Altered T4 absorption owing to modified gastric physiology comes up as one of the critical reasons for increased thyroxine requirement.
“Among those, altered T4 absorption owing to modified gastric physiology comes up as one of the critical reasons (Centanni et al., 2006; Seng Yue et al., 2015).”
From Thyroid disorders and gastrointestinal dysmotility: an old association (2024) · cites this paper as Seng Yue et al., 2015
Elevated pH due to H. pylori infection, autoimmune gastritis, and proton pump inhibitors antagonizes subsequent LT4 absorption.
“Several studies have demonstrated that an elevated pH due to Heliobacter pylori infection, autoimmune gastritis, and proton pump inhibitors (PPIs) antagonize the subsequent absorption (11–13).”
From Levothyroxine: conventional and novel drug delivery formulations. (2023) · cites this paper as [11]
IV esomeprazole decreased the maximum serum concentration (Cmax) and the area under the curve (AUC) from 0 to 12 hours by 12.7% and 14.8%, respectively, in healthy volunteers taking LT4 tablets.
“A randomized crossover study demonstrated that IV esomeprazole could decrease the maximum serum concentration (Cmax) and the area under the curve (AUC) from 0 to 12 hours by 12.7% and 14.8%, respectively, in healthy volunteers taking LT4 tablets (11).”
From Levothyroxine: conventional and novel drug delivery formulations. (2023) · cites this paper as [11]
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).”
From Levothyroxine: conventional and novel drug delivery formulations. (2023) · cites this paper as [11]
The pharmacokinetic equivalence of different formulations in healthy volunteers may not translate to equivalence in patients, especially in those with malabsorption.
“In addition, the pharmacokinetic equivalence of different formulations in healthy volunteers may not translate to equivalence in patients, especially in those with malabsorption (11).”
From Levothyroxine: conventional and novel drug delivery formulations. (2023) · cites this paper as [11]
Only 2 studies were well designed (randomized and crossover).
“Only 2 studies were well designed (randomized and crossover) (11, 98).”
From Levothyroxine: conventional and novel drug delivery formulations. (2023) · cites this paper as [11]
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.”
From Levothyroxine: conventional and novel drug delivery formulations. (2023) · cites this paper as [11]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
The epidemiology of thyroid disease
Vanderpump, M. P. J. (2011) · British Medical Bulletin · doi:10.1093/bmb/ldr030 · Cited by 1,179 · see citing works
The Incidence and Prevalence of Thyroid Dysfunction in Europe: A Meta-Analysis
Garmendia Madariaga, A., Santos Palacios, S., Guillén-Grima, F., & Galofré, J. C. (2014) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2013-2409 · Cited by 800 · see citing works
Thyroxine in Goiter, <i>Helicobacter pylori</i> Infection, and Chronic Gastritis
Centanni, M., Gargano, L., Canettieri, G., Viceconti, N., Franchi, A., Fave, G. D., & Annibale, B. (2006) · New England Journal of Medicine · doi:10.1056/nejmoa043903 · Cited by 329 · see citing works
Conditions and drugs interfering with thyroxine absorption
Liwanpo, L., & Hershman, J. M. (2009) · Best Practice & Research Clinical Endocrinology & Metabolism · doi:10.1016/j.beem.2009.06.006 · Cited by 222 · see citing works
Hypothyroidism: etiology, diagnosis, and management
Almandoz, J. P., & Gharib, H. (2012) · Medical Clinics of North America · doi:10.1016/j.mcna.2012.01.005 · Cited by 216 · see citing works
A review of the pharmacokinetics of levothyroxine for the treatment of hypothyroidism
Colucci, P., Yue, C. S., Ducharme, M., Benvenga, S., Principal Scientist, L. A. C. I., Principal Scientist, L. A. C. I. A. P. C., President and CEO, L. A. C. I., & Professor of Medicine, D. (2010) · European Endocrinology · doi:10.17925/ee.2013.09.01.40 · Cited by 167 · see citing works
Self-citationPabla, D., Akhlaghi, F., & Zia, H. (2009) · European Journal of Pharmaceutics and Biopharmaceutics · doi:10.1016/j.ejpb.2008.10.008 · Cited by 124 · see citing works
Sachmechi, I., Reich, D. M., Aninyei, M., Wibowo, F., Gupta, G., & Kim, P. J. (2007) · Endocrine Practice · doi:10.4158/ep.13.4.345 · Cited by 112 · see citing works
When thyroid hormone replacement is ineffective?
Benvenga, S. (2013) · Current Opinion in Endocrinology, Diabetes & Obesity · doi:10.1097/med.0000000000000003 · Cited by 74 · see citing works
A. Irving, S., Vadiveloo, T., & Leese, G. P. (2015) · Clinical Endocrinology · doi:10.1111/cen.12559 · Cited by 69 · see citing works
Thyroxine softgel capsule in patients with gastric-related T4 malabsorption
Santaguida, M. G., Virili, C., Duca, S. C. D., Cellini, M., Gatto, I., Brusca, N., De Vito, C., Gargano, L., & Centanni, M. (2015) · Endocrine · doi:10.1007/s12020-014-0476-7 · Cited by 68 · see citing works
Vita, R., & Benvenga, S. (2014) · Endocrine Practice · doi:10.4158/ep13316.cr · Cited by 60 · see citing works
Self-citationColucci, P., D'Angelo, P., Mautone, G., Scarsi, C., & Ducharme, M. P. (2011) · Therapeutic Drug Monitoring · doi:10.1097/ftd.0b013e318217b69f · Cited by 45 · see citing works
Absorption Kinetics of Levothyroxine Is Not Altered by Proton-pump Inhibitor Therapy
Dietrich, J. W., Gieselbrecht, K., Holl, R. W., & Boehm, B. O. (2006) · Hormone and Metabolic Research · doi:10.1055/s-2006-924980 · Cited by 44 · see citing works
Trifirò, G., Parrino, F., Sultana, J., Giorgianni, F., Ferrajolo, C., Bianchini, E., Medea, G., Benvenga, S., Cricelli, I., Cricelli, C., et al. (2015) · Clinical Drug Investigation · doi:10.1007/s40261-015-0271-0 · Cited by 40 · see citing works
The Effect of Famotidine, Esomeprazole, and Ezetimibe on Levothyroxine Absorption
Ananthakrishnan, S., Braverman, L. E., Levin, R. M., Magnani, B., & Pearce, E. N. (2008) · Thyroid · doi:10.1089/thy.2007.0381 · Cited by 38 · see citing works
Aghazadeh‐Habashi, A., & Jamali, F. (2008) · European Journal of Pharmaceutics and Biopharmaceutics · doi:10.1016/j.ejpb.2008.07.013 · Cited by 26 · see citing works
Flagged first, then by citations
1 of the 18 references couldn’t be matched to a known paper.
Cited by
Sorted by citations
Chaker, L., Bianco, A. C., Jonklaas, J., & Peeters, R. P. (2017) · The Lancet · doi:10.1016/s0140-6736(17)30703-1 · Cited by 1,159 · see citing works
Factors Affecting Gastrointestinal Absorption of Levothyroxine: A Review
Skelin, M., Lucijanić, T., Amidžić Klarić, D., Rešić, A., Bakula, M., Liberati-Čizmek, A.-M., Gharib, H., & Rahelić, D. (2017) · Clinical Therapeutics · doi:10.1016/j.clinthera.2017.01.005 · Cited by 133 · see citing works
The activities of drug inactive ingredients on biological targets
Pottel, J., Armstrong, D., Zou, L., Fekete, A., Huang, X., Torosyan, H., Bednarczyk, D., Whitebread, S., Bhhatarai, B., Liang, G., et al. (2020) · Science · doi:10.1126/science.aaz9906 · Cited by 90 · see citing works
New Formulations of Levothyroxine in the Treatment of Hypothyroidism: Trick or Treat?
Nagy, E. V., Perros, P., Papini, E., Katkó, M., & Hegedűs, L. D. (2020) · Thyroid · doi:10.1089/thy.2020.0515 · Cited by 65 · see citing works
Levothyroxine: conventional and novel drug delivery formulations.
Liu, H., Li, W., Zhang, W., Sun, S., & Chen, C. (2023) · Endocrine Reviews · doi:10.1210/endrev/bnac030 · Cited by 63 · see citing works
Doki, K., Darwich, A. S., Patel, N. K., & Rostami‐Hodjegan, A. (2017) · European Journal of Pharmaceutical Sciences · doi:10.1016/j.ejps.2017.07.035 · Cited by 56 · see citing works
Levothyroxine therapy in gastric malabsorptive disorders
Virili, C., Brusca, N., Capriello, S., & Centanni, M. (2021) · Frontiers in Endocrinology · doi:10.3389/fendo.2020.621616 · Cited by 52 · see citing works
Cristofoletti, R., Patel, N. K., & Dressman, J. (2016) · Journal of Pharmaceutical Sciences · doi:10.1016/j.xphs.2016.10.008 · Cited by 50 · see citing works
Thyroid disorders and gastrointestinal dysmotility: an old association
Xu, G.-M., Hu, M.-X., Li, S.-Y., Ran, X., Zhang, H., & Ding, X.-F. (2024) · Frontiers in Physiology · doi:10.3389/fphys.2024.1389113 · Cited by 43 · see citing works
Levothyrox® New and Old Formulations: Are they Switchable for Millions of Patients?
Concordet, D., Gandia, P., Montastruc, J., Bousquet‐mélou, A., Lees, P., Ferran, A. A., & Toutain, P. (2019) · Clinical Pharmacokinetics · doi:10.1007/s40262-019-00747-3 · Cited by 42 · see citing works
Novel thyroxine formulations: a further step toward precision medicine
Virili, C., Trimboli, P., & Centanni, M. (2019) · Endocrine · doi:10.1007/s12020-019-02049-x · Cited by 41 · see citing works
Guglielmi, R., Frasoldati, A., Zini, M., Grimaldi, F., Gharib, H., Garber, J. R., & Papini, E. (2016) · Endocrine Practice · doi:10.4158/ep161308.or · Cited by 39 · see citing works
Centanni, M., Duntas, L., Feldt-Rasmussen, U., Koehrle, J., Peeters, R. P., Razvi, S., Trimboli, P., & Virili, C. (2025) · European Thyroid Journal · doi:10.1530/etj-25-0123 · Cited by 38 · see citing works
“However, it is known that chemical equivalence does not automatically correspond to bioequivalence, which is determined by pharmacokinetic tests on healthy volunteers (28) but may differ from actual bioequivalence in patients in different clinical settings (29).”
Tanguay, M., Girard, J., Scarsi, C., Mautone, G., & Larouche, R. (2019) · Clinical Pharmacology in Drug Development · doi:10.1002/cpdd.608 · Cited by 33 · see citing works
Medications and Food Interfering with the Bioavailability of Levothyroxine: A Systematic Review
Liu, H., Lu, M., Hu, J., Fu, G., Feng, Q., Sun, S., & Chen, C. (2023) · Therapeutics and Clinical Risk Management · doi:10.2147/tcrm.s414460 · Cited by 29 · see citing works
Ernst, F. R., Sandulli, W., Elmor, R., Welstead, J., Sterman, A. B., & Lavan, M. (2017) · Drugs in R&D · doi:10.1007/s40268-016-0150-z · Cited by 23 · see citing works
Levothyroxine treatment and gastric juice pH in humans: the proof of concept
Virili, C., Bruno, G., Santaguida, M. G., Gargano, L., Stramazzo, I., De Vito, C., Cicenia, A., Scalese, G., Porowska, B., Severi, C., et al. (2022) · Endocrine · doi:10.1007/s12020-022-03056-1 · Cited by 22 · see citing works
Trimboli, P., Virili, C., Centanni, M., & Giovanella, L. (2018) · Frontiers in Endocrinology · doi:10.3389/fendo.2018.00118 · Cited by 21 · see citing works
Benvenga, S., Capodicasa, G., & Perelli, S. (2017) · Frontiers in Endocrinology · doi:10.3389/fendo.2017.00321 · Cited by 18 · see citing works
Self-citationBenvenga, S. (2019) · Journal of Clinical & Translational Endocrinology · doi:10.1016/j.jcte.2019.100204 · Cited by 17 · see citing works
Guzmán-Prado, Y., Vita, R., & Samson, O. (2021) · Journal of General Internal Medicine · doi:10.1007/s11606-020-06403-y · Cited by 15 · see citing works
Refractory hypothyroidism: unraveling the complexities of diagnosis and management
Quiroz-Aldave, J. E., Concepción-Zavaleta, M. J., Durand-Vásquez, M. D. C., Concepción-Urteaga, L. A., Gamarra-Osorio, E. R., Suárez-Rojas, J., Rafael-Robles, L. D. P., Paz-Ibarra, J., & Román-González, A. (2023) · Endocrine Practice · doi:10.1016/j.eprac.2023.09.003 · Cited by 14 · see citing works
New Drug Delivery Systems for Stable Oral Absorption: Theory, Strategies, and Applications
Onoue, S. (2024) · Biological and Pharmaceutical Bulletin · doi:10.1248/bpb.b24-00566 · Cited by 12 · see citing works
Trimboli, P., & Mouly, S. J. (2022) · Journal of Clinical Medicine · doi:10.3390/jcm11123479 · Cited by 11 · see citing works
Oteri, V., Volpe, S., Lopes, M., Sceusa, G., Tumminia, A., Belfiore, A., Frasca, F., & Gullo, D. (2024) · Endocrine · doi:10.1007/s12020-024-04016-7 · Cited by 9 · see citing works
Daily requirement of softgel thyroxine is independent from gastric juice pH
Virili, C., Capriello, S., Stramazzo, I., Brusca, N., Santaguida, M. G., Gargano, L., Bagaglini, M. F., Bruno, G., Severi, C., & Centanni, M. (2022) · Frontiers in Endocrinology · doi:10.3389/fendo.2022.1002583 · Cited by 8 · see citing works
Elmor, R., Sandulli, W., & Carter, C. A. (2017) · Pharmacoeconomics open access · doi:10.4172/2472-1042.1000113 · Cited by 10 · see citing works
Sachmechi, I., Lucas, K. J., Stonesifer, L. D., Ansley, J. F., Sack, P., Celi, F. S., Scarsi, C., Lanzi, G., Wartofsky, L., & Burman, K. D. (2023) · Thyroid · doi:10.1089/thy.2023.0382 · Cited by 7 · see citing works
Yue, C. S., Scarsi, C., Bettazzi, E., Mautone, G., Celi, F. S., & Ducharme, M. P. (2024) · Endocrine Practice · doi:10.1016/j.eprac.2024.03.388 · Cited by 4 · see citing works
Ozdin, D., Ducharme, M. P., Varin, F., Fuglsang, A., & Al-Numani, D. (2020) · Journal of Pharmacy & Pharmaceutical Sciences · doi:10.18433/jpps30872 · Cited by 3 · see citing works
Concordet, D., Gandia, P., Montastruc, J., Bousquet‐mélou, A., Lees, P., Ferran, A. A., & Toutain, P. (2019) · Clinical Pharmacokinetics · doi:10.1007/s40262-019-00786-w · Cited by 3 · see citing works
Awasthi, A., Chakraborty, P. P., Agrawal, N., Sinha, A., Pandey, A. K., & Maiti, A. (2023) · Thyroid Research · doi:10.1186/s13044-023-00156-6 · Cited by 3 · see citing works
One sip of water with LT-4 supplementation—a key to euthyroidism in Hashimoto’s thyroiditis
Schnedl, W. J., Michaelis, S., Mangge, H., & Enko, D. (2024) · Endocrine · doi:10.1007/s12020-024-03829-w · Cited by 1 · see citing works
Thyrogastric syndrome: a modern view of the problem
Troshina, E. A., Botasheva, M. H., Mazurina, N. V., Leites, Y. G., & Galeev, A. S. (2025) · Clinical and experimental thyroidology · doi:10.14341/ket12827 · Cited by 1 · see citing works
Höcht, C., Tripodi, V. P., & Lucangioli, S. E. (2021) · Springer eBooks · doi:10.1007/978-3-030-51519-5_135-1 · Cited by 1 · see citing works
汚染防止形ふっ素樹脂塗料「Vフロン#200クリーン」 建築外装用ふっ素樹脂塗料で塗膜の汚れ防止
畑中, 昭., & 水野民雄 (1998) · 建築設備と配管工事
Höcht, C., Tripodi, V. P., & Lucangioli, S. E. (2022) · Springer eBooks · doi:10.1007/978-3-030-84860-6_135
Kawkgi, O. M. E. (2024) · Clinical Thyroidology · doi:10.1089/ct.2024;36.51-54
The Relationship Between Hypothyroidism and Pneumonia and Possible Prevention and Treatment Measures
Hao, Y., Zheng, H., Xiang, W., Chen, F., & Qiang, G. (2025) · International Journal of General Medicine · doi:10.2147/ijgm.s529705
Awasthi, A., Chakraborty, P. P., Agrawal, N., Sinha, A., Pandey, A. K., & Maiti, A. (2023) · Figshare · doi:10.6084/m9.figshare.23273466
Refractory hypothyroidism: Diagnostic evaluation and management strategies
Mavromati, M., Jarlborg, P., Demarchi, M. S., & Leboulleux, S. (2026) · Annales d Endocrinologie · doi:10.1016/j.ando.2026.102489
- Authors
- Seng Yue, C., Benvenga, S., Scarsi, C., Loprete, L., & Ducharme, M.
- Affiliations
- University of Messina (IT)
- IBSA Institut Biochimique (Switzerland) (CH)
- Université de Montréal (CA)
- Venue
- Journal of Pharmacy & Pharmaceutical Sciences
- Publisher
- Frontiers Media SA
- Published
- 2015-11-26
- Volume
- 18
- Issue
- 5
- Pages
- 844
- ISSN
- 1482-1826 (ISSN-L)
- OpenAlex
- W2179799499
- Cited by
- 41
- References
- 18
- Citations by year
- 2026: 1 · 2025: 3 · 2024: 6 · 2023: 5 · 2022: 5 · 2021: 3 · 2020: 3 · 2019: 4 · 2018: 2 · 2017: 5 · 2016: 3
- FWCI
- 2.89
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by
- Locations
- Journal of Pharmacy & Pharmaceutical Sciences (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Disorders and Treatments
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmaceutical Science › Drug Solubulity and Delivery Systems
- Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Pharmaceutical studies and practices
- Keywords
- levothyroxine, bioequivalence, gastric pH, esomeprazole, proton pump inhibitors, pharmacokinetics, drug formulation, healthy volunteers, thyroid hormone replacement, Cmax, AUC, Tmax, crossover design, washout period
- MeSH terms
- Adolescent, Adult, Capsules, Drug Interactions, Gastric Acid, Humans, Male, Tablets, Therapeutic Equivalency, Thyroxine, Cross-Over Studies, Area Under Curve, Proton Pump Inhibitors, Young Adult, Esomeprazole, Healthy Volunteers
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
