Tadalafil pharmacokinetics in healthy subjects

• Published in: British journal of clinical pharmacology 2006-03, Vol.61 (3), p.280-288
• Main Authors: Forgue, S. Thomas, Patterson, Beverley E., Bedding, Alun W., Payne, Christopher D., Phillips, Diane L., Wrishko, Rebecca E., Mitchell, Malcolm I.
• Format: Article
• Language: English
• Subjects: Adolescent; Adult; Aged; Biological and medical sciences; Biological Availability; Body Mass Index; Carbolines - adverse effects; Carbolines - blood; Carbolines - pharmacokinetics; Circadian Rhythm - physiology; Cross-Over Studies; Dose-Response Relationship, Drug; Drug Administration Schedule; Eating - physiology; erectile dysfunction; Female; Humans; Male; Medical sciences; Metabolic Clearance Rate; Middle Aged; Pharmacokinetics; Pharmacology. Drug treatments; phosphodiesterase; Phosphodiesterase Inhibitors - adverse effects; Phosphodiesterase Inhibitors - blood; Phosphodiesterase Inhibitors - pharmacokinetics; Tadalafil
• ISSN: 0306-5251; 1365-2125
• DOI: 10.1111/j.1365-2125.2005.02553.x

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 t1/2. 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.