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Tadalafil pharmacokinetics in healthy subjects
Open accessAbstract
Aims: To characterize tadalafil plasma pharmacokinetics in healthy subjects following single and multiple doses. Methods: Noncompartmental parameters were calculated for healthy subjects receiving a single 2.5–20‐mg tadalafil dose in 13 clinical pharmacology studies. An integrated statistical analysis of results in 237 subjects provided global averages and an assessment of effects of body mass index (BMI), age, gender and smoking status. Diurnal variation, food effects and proportionality of exposure to dose were analysed in three studies. Multiple‐dose pharmacokinetics were evaluated in a separate study in which parallel groups of 15 subjects received 10 or 20 mg tadalafil once daily for 10 days. Results: Tadalafil was absorbed rapidly with mean Cmax (378 µg l−1 for 20 mg) observed at 2 h; thereafter, concentrations declined nearly monoexponentially with a mean (5th, 95th percentiles) t1/2 of 17.5 (11.5, 29.6) hours. Mean oral clearance (CL/F) was 2.48 (1.35, 4.35) l h−1 and apparent volume of distribution (Vz/F) was 62.6 (39.5, 92.1) l. No clinically meaningful effect of BMI, age, gender or smoking was identified. Exposure was not substantially affected by time of dosing. Food had negligible effects on bioavailability as assessed by 90% confidence intervals for Cmax and AUC mean ratios. Parameters were proportional to dose, indicating that doubling the dose doubled exposure. Steady state was attained by day 5 following once‐daily administration, and accumulation (1.6‐fold) was consistent with the t 1/2. Conclusions: Tadalafil pharmacokinetics are linear with respect to dose and time, and are not affected by food. Systemic clearance is low relative to other phosphodiesterase 5 inhibitors.
Overview
CoChat Summary
TL;DR
Tadalafil pharmacokinetics in healthy subjects are linear with respect to dose and time, with low oral clearance and a prolonged half-life. Food has negligible effect, and once-daily dosing reaches steady state by day 5 with approximately 1.6-fold accumulation.
Key findings
- After a single 20-mg dose, mean Cmax was 378 µg l⁻¹ at median tmax 2 h; mean t₁/₂ was 17.5 h (5th, 95th percentiles 11.5, 29.6), CL/F was 2.48 l h⁻¹ (1.35, 4.35), and Vz/F was 62.6 l (39.5, 92.1).
- Exposure was proportional to dose: doubling the dose increased AUC by 1.96-fold (1.90, 2.02), with β = 0.97 (0.93, 1.01); Cmax increased slightly less than proportionally, by 1.84-fold (1.77, 1.91).
- Food had negligible effect: fed/fasted geometric mean ratios were 1.08 (1.02, 1.15) for AUC and 1.16 (1.07, 1.26) for Cmax, within prespecified equivalence limits. Evening/morning ratios were 0.81 (0.73, 0.90) for AUC and 0.79 (0.71, 0.89) for Cmax, suggesting slightly lower evening bioavailability.
- With 10- or 20-mg once-daily dosing, steady state was attained by day 5; accumulation from day 1 to day 10 was approximately 1.6-fold, and day 10 t₁/₂, CL/F, and Vz/F were similar to single-dose values.
Methods
- Noncompartmental pharmacokinetic parameters were calculated from 13 single-dose clinical pharmacology studies in healthy subjects; an integrated statistical analysis included 237 subjects (186 males), with 45 subjects contributing data from two dosing occasions, and assessed BMI, age, gender, and smoking status.
- Three studies evaluated diurnal effects (12 subjects, 10 mg), definitive food effects (18 subjects, 20 mg fed vs fasted), and dose proportionality (16 subjects, single 2.5-, 5-, 10-, and 20-mg doses in a four-period crossover).
- A separate multiple-dose study randomized 65 healthy subjects to 10 or 20 mg tadalafil once daily for 10 days; 30 subjects participated in the pharmacokinetic assessment. Plasma tadalafil was measured by validated HPLC-MS/MS, and analyses used mixed-effects models, a power model for dose proportionality, and prespecified equivalence confidence intervals.
Limitations
- The paper states that absolute bioavailability of tadalafil following oral dosing has not been determined in any clinical study.
- The paper states that the report does not address populations with erectile dysfunction, hypertension, diabetes, renal insufficiency, hepatic impairment, or CYP3A inducer/inhibitor drug interactions.
- Evident from the text: the integrated analysis was in healthy volunteers who were predominantly Caucasian (228/237) and male (186/237), and several substudies were small (diurnal n = 12; food effect n = 18; dose proportionality n = 16), which limits generalizability.
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0 Valid · 0 Not valid · 16 Not checked · 44 Own results and interpretations
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In the paper
“Age, gender and smoking status were also significant covariates; the magnitude of effects is summarized in Table 4.”
§ Tadalafil pharmacokinetics in healthy subjects > Integrated statistical analysis
plainstates an association- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper states — it cites no source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“There was no significant difference between t max values.”
§ Tadalafil pharmacokinetics in healthy subjects > Food effect
plainn = 18- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
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In the paper
“The most frequently reported treatment-emergent adverse events in the study of once-daily dosing for 10 days were: headache (66% of 65 subjects), back pain (60%), myalgia (43%) dyspepsia (19%), nausea (19%), dizziness (17%), fatigue (12%), eye pain (11%) and spontaneous penile erection (11%).”
§ Tadalafil pharmacokinetics in healthy subjects > Safety and tolerability
plainn = 65- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
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In the paper
“Inspection of the distribution of individual dose-normalized AUC values suggested that exposure was proportional to dose across the eightfold range (2.5-20 mg) (Figure 1).”
- Also stated in: § Dose proportionality · boosted
“Proportionality was concluded since the 95% CI for the slope [ β = 0.97 (0.93, 1.01)] for regression of ln(AUC) on ln(dose) was completely contained within the prespecified equivalence interval.”
§ Tadalafil pharmacokinetics in healthy subjects > Dose proportionality
boostedstates an associationn = 16- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Also stated in: § Dose proportionality · boosted
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Mean oral clearance (CL/F) was 2.48 (1.35, 4.35) l h -1”
§ Tadalafil pharmacokinetics in healthy subjects > Abstract
plainn = 237- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
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Claims other papers make about this one
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In the citing paper
“Additionally, at steady-state concentration, the daily exposure is 1.6-fold greater than the same dose taken intermittently (Forgue et al 2006).”
From Tadalafil in the treatment of erectile dysfunction (2008) · cites this paper as Forgue et al 2006
In the citing paper
“The 17.5 hour half-life of tadalafil lends itself to daily dosing because steady-state plasma concentrations are attained within five days of initiating daily dosing (Forgue et al 2006).”
From Tadalafil in the treatment of erectile dysfunction (2008) · cites this paper as Forgue et al 2006
In the citing paper
“Previous bioequivalence clinical trials reported no differences in tadalafil pharmacokinetics between fed and fasted conditions [44,45].”
From Food Administration and Not Genetic Variants Causes Pharmacokinetic Variability of Tadalafil and Finasteride (2023) · cites this paper as [44]
Self-check
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In the paper
§ Tadalafil pharmacokinetics in healthy subjects > Discussion
“Rate and extent of tadalafil absorption in the morning were slightly lower than in the evening.”
§ Tadalafil pharmacokinetics in healthy subjects > Morning vs. evening administration
“The evening/morning ratio (90% CI) of LS means was 0.81 (0.73, 0.90) for AUC and 0.79 (0.71, 0.89) for C max , suggesting slightly lower bioavailability in the evening.”
Citations
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Self-citation
Research works printed but not linked: 5
- Ring BJ, 2004, Identification of the human cytochrome P450 (CYP) responsible for the formation of the major oxidative metabolite of tadalafil (Cialis), Drug Metab Rev, 36, 70
- Phillips DL, 2004, Metabolism and excretion of tadalafil in healthy men after oral administration of 100 mg [14C]‐tadalafil, The AAPS J, 6
- Patterson B, 2001, Dose‐normalized pharmacokinetics of tadalafil (IC351) administered as a single dose to healthy volunteers, Int J Impotence Res, 13, S32
- 2002, Guidance for Industry, Food‐Effect Bioavailability and Fed Bioequivalence Studies.
- Angulo J, 2001, IC351 enhances nitric oxide‐mediated relaxation of human arterial and trabecular penile smooth muscle, Diabetologia, 44, A295
Cited by
Guidelines on male sexual dysfunction: erectile dysfunction and premature ejaculation
Hatzimouratidis, K., Amar, E., Eardley, I., Giuliano, F., Hatzichristou, D., Montorsi, F., Vardi, Y., & Wespes, E. (2010) · European Urology · doi:10.1016/j.eururo.2010.02.020 · Cited by 1,223
Tadalafil Relieves Lower Urinary Tract Symptoms Secondary to Benign Prostatic Hyperplasia
McVary, K. T., Roehrborn, C. G., Kaminetsky, J. C., Auerbach, S. M., Wachs, B., Young, J. M., Esler, A., Sides, G. D., & Denes, B. S. (2007) · Journal of Urology · doi:10.1016/j.juro.2006.11.037 · Cited by 302
Roehrborn, C. G., McVary, K. T., Elion-Mboussa, A., & Viktrup, L. (2008) · Journal of Urology · doi:10.1016/j.juro.2008.06.079 · Cited by 223
Phosphodiesterases as Therapeutic Targets for Alzheimer's Disease
García‐Osta, A., Cuadrado‐Tejedor, M., García, C., Oyarzábal, J., & Franco, R. (2012) · ACS Chemical Neuroscience · doi:10.1021/cn3000907 · Cited by 266
Weed, D. T., Vella, J. L., Reis, I. M., De la fuente, A. C., Gomez, C., Sargi, Z., Nazarian, R., Califano, J., Borrello, I., & Serafini, P. (2015) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-14-1711 · Cited by 261
Metadata
- Authors
- Forgue, S. T., Patterson, B. E., Bedding, A. W., Payne, C. D., Phillips, D. L., Wrishko, R. E., & Mitchell, M. I.
- Affiliations
- Eli Lilly (United States) (US)
- Corresponding author
- Forgue, S. Thomas
- Venue
- British Journal of Clinical Pharmacology
- Publisher
- Wiley
- Published
- 2005-12-20
- Volume
- 61
- Issue
- 3
- Pages
- 280-288
- ISSN
- 0306-5251 (ISSN-L)
- 1365-2125
- PMC
- PMC1885023
- OpenAlex
- W1975119053
- Semantic Scholar
- 702568e16e387fed970d136848a9542c93c3e0c0
- Cited by
- 284
- References
- 26
- Citations by year
- 2026: 12 · 2025: 13 · 2024: 20 · 2023: 17 · 2022: 13 · 2021: 14 · 2020: 17 · 2019: 18 · 2018: 14 · 2017: 12 · 2016: 13 · 2015: 11 · 2014: 21 · 2013: 13 · 2012: 11
- FWCI
- 5.31
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- British Journal of Clinical Pharmacology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (publishedVersion)
- Funders
- Eli Lilly and Company
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Sexual function and dysfunction studies
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
- Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Pharmaceutical studies and practices
- Keywords
- tadalafil, pharmacokinetics, phosphodiesterase-5 inhibitors, oral bioavailability, food effect, dose proportionality, steady-state pharmacokinetics, body mass index, smoking, age and gender effects, healthy volunteers
- MeSH terms
- Tadalafil, Adolescent, Adult, Aged, Biological Availability, Carbolines, Circadian Rhythm, Dose-Response Relationship, Drug, Drug Administration Schedule, Eating, Female, Humans, Male, Metabolic Clearance Rate, Middle Aged, Phosphodiesterase Inhibitors, Body Mass Index, Cross-Over Studies
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- Forgue, S. T., Patterson, B. E., Bedding, A. W., Payne, C. D., Phillips, D. L., Wrishko, R. E., & Mitchell, M. I. (2006). Tadalafil pharmacokinetics in healthy subjects. British Journal of Clinical Pharmacology. https://doi.org/10.1111/j.1365-2125.2005.02553.x
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