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.

In vitro results suggested that tadalafil would have little effect on the pharmacokinetics of drugs metabolized by CYP3A. Clinical studies demonstrated that the pharmacokinetics of 2 different CYP3A substrates, midazolam and lovastatin, were virtually unchanged after tadalafil coadministration. Thus therapeutic concentrations of tadalafil do not produce clinically significant changes in the clearance of drugs metabolized by CYP3A.

AimsTo evaluate the effects of gender, age, diabetes mellitus, renal and hepatic impairment on tadalafil pharmacokinetics and tolerability. MethodsSix single-dose (5, 10 or 20 mg orally) clinical pharmacology studies were conducted in the UK, Belgium, Poland and Germany in healthy male and female subjects, elderly subjects and subjects with diabetes mellitus, renal impairment, end-stage renal failure (ESRF) or hepatic impairment. The gender study also incorporated administration of 10 mg tadalafil daily for 10 days. ResultsSystemic exposure in the elderly was 25% greater than in young subjects (mean AUC ratio 1.25; 90% confidence interval 0.972, 1.61). The AUC was 19% lower in subjects with diabetes mellitus than in healthy age/gender-matched controls. Pharmacokinetics in female subjects were essentially similar to those in males. Exposure in subjects with mild or moderate renal insufficiency was approximately twice that in healthy subjects. The mean AUC for the major metabolite (total methylcatechol glucuronide) in the presence of ESRF was three times the mean for healthy subjects. Haemodialysis contributed negligibly to elimination of tadalafil or the metabolite. Hepatic impairment had negligible effects on exposure. The most common adverse events in these six studies were headache, back pain and myalgia. A 10-mg dose was not well tolerated by subjects with moderate renal dysfunction in this study. ConclusionsNo clinically significant effect of gender, age, diabetes mellitus or hepatic impairment on tadalafil pharmacokinetics was observed. Renal insufficiency resulted in increased systemic exposure. Tadalafil was not associated with any serious clinically significant adverse events or study discontinuations due to adverse events.

The present work introduces a new method to model the pharmacokinetics (PK) and pharmacodynamics (PD) of an inhaled dose of bronchodilator, alternative to classic compartmental representations or computational fluid dynamics. A five compartment PK model comprising alimentary tract absorption (gut), bronchial tree mucosa, bronchial muscles, plasma, and elimination/excretion pathways has been developed. Many anatomical and physiological features of the bronchial tree depend on bronchial generation or on mean distance from the larynx. Among these are diameters, resistances, and receptor density, which determine together the local response to the inhaled drug; integrating these local responses over the whole bronchial tree allows an approximation of total bronchodilator response and airflow resistance. While the PK part of the model reflects classical compartmental assumptions, the PD part adds a simplified geometrical and functional description of the bronchial tree to a typical empirical model of local effect on bronchial muscle, leading to the direct computation of the approximate forced expiratory volume in 1 s (FEV(1)). In the present work the construction of the model is detailed, with reference to literature data. Simulation of a hypothetical asthmatic subject is employed to illustrate the behaviour of the model in representing the evolution over time of the distribution and pharmacological effect of an inhaled dose of a bronchodilator. The relevance of particle size and drug formulation diffusivity on therapeutic efficacy is discussed.