Tadalafil pharmacokinetics in healthy subjects

Abstract

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.

Patients’ preference in the treatment of erectile dysfunction: a critical review of the literature

“…Among the patients who had the opportunity to try a cycle of therapy with tadalafil, 66-90% decided to continue their treatment with tadalafil, or switch to tadalafil. Patients on tadalafil may be less concerned about the time between dosing and intercourse, likely because of longer period of responsiveness for tadalafil 11 and the drug can be taken without regard to food intake, 13 in contrast to sildenafil and vardenafil, for which heavy-fat meals have been shown to decrease the extent and slow the rate of absorption. 14,41 The fact that convenience, simplicity and naturalness are traits that men value in an ED treatment 32 could, therefore, have contributed to more tadalafil patients being satisfied with their treatment, thereby resulting in less patients switching from tadalafil, as compared with sildenafil or vardenafil.…”

“…PDE-5 inhibitors differ mainly in half-life (that is, sildenafil and vardenafil B4 h and tadalafil B17.5 h), known duration of action and dietary effects on absorption. [13][14][15] In ED, where the patients' subjective perception is very important, the objective of treatment should not only be 'organ focused', that is, facilitating the erection, but should also be 'patient-outcome oriented'. Patients' satisfaction with sexual intercourse, their overall sex lives and ED treatments may represent reliable predictors of key patient-related treatment outcomes, in addition to pharmacological efficacy and safety.…”

Do vardenafil and tadalafil have advantages over sildenafil in the treatment of erectile dysfunction?

“…27 A sublingual preparation of sildenafil has been developed, and this will not be affected by food. An initial study with sublingual sildenafil (20 mg) has shown that the mean onset of action was 15.5 min and lasted for an average of 40 min with 13/20 of subjects with ED achieving erections.…”

Contribution of CYP3A Isoforms to Dealkylation of PDE5 Inhibitors: A Comparison between Sildenafil N-Demethylation and Tadalafil Demethylenation

“…7) In contrast, tadalafil has the advantage of once a day dosing compared to sildenafil's three times a day dosing, with implications for patient convenience and compliance. 6,8) Therefore, a transition from sildenafil to tadalafil has been frequently tried in stable patients with PAH. 3,8) In humans, sildenafil is eliminated predominantly by hepatic metabolism and is converted to an active metabolite, N-desmethyl sildenafil, with properties similar to the parent drug.…”

“…3,4) That is, sildenafil has a fairly short half-life of about 4-5 h, whereas tadalafil has a long half-life of about 17.5 h in healthy subjects. 5,6) The short half-life of sildenafil makes it the drug of choice in patients with more severe cardiovascular disease, allowing early use of supportive treatment if an adverse clinical event occurs. 7) In contrast, tadalafil has the advantage of once a day dosing compared to sildenafil's three times a day dosing, with implications for patient convenience and compliance.…”