What are the pharmacokinetics of Tadalafil (Cialis)?

From the Guidelines

Tadalafil has a half-life of approximately 17.5 hours, which allows for once-daily dosing and provides a longer window of effectiveness compared to other phosphodiesterase type 5 (PDE5) inhibitors. The pharmacokinetics of tadalafil are characterized by rapid absorption after oral administration, with peak plasma concentrations occurring within 2-8 hours 1.

Key Pharmacokinetic Properties

• The drug is primarily metabolized by the cytochrome P450 enzyme CYP3A4 in the liver, with approximately 36% of the dose excreted in feces and 61% in urine as metabolites.
• Tadalafil's steady-state volume of distribution is about 63 L, indicating good tissue distribution, and it is highly protein-bound (94%) in plasma.
• Its prolonged duration of action results from its pharmacokinetic profile, particularly its extended half-life, which explains why its effects can last up to 36 hours after dosing.

Clinical Considerations

• In patients with renal or hepatic impairment, dose adjustments may be necessary due to potentially increased drug exposure.
• Tadalafil is contraindicated in patients using nitrates or guanylate cyclase stimulators and in those with cardiac disease, hypotension, poorly controlled blood pressure, recent stroke (<6 mo), or significant hepatic or renal insufficiency 1.
• The most frequently reported adverse events (AEs) in men using tadalafil include dyspepsia, headache, flushing, back pain, nasal congestion, myalgia, visual disturbance, and dizziness 1.

Summary of Key Points

• Tadalafil has a long half-life of approximately 17.5 hours.
• It is rapidly absorbed after oral administration.
• The drug is primarily metabolized by the cytochrome P450 enzyme CYP3A4 in the liver.
• Tadalafil's steady-state volume of distribution is about 63 L.
• It is highly protein-bound (94%) in plasma.
• Its effects can last up to 36 hours after dosing.

From the FDA Drug Label

Over a dose range of 2.5 mg to 20 mg, tadalafil exposure (AUC) increases proportionally with dose in healthy subjects. Steady-state plasma concentrations are attained within 5 days of once per day dosing and exposure is approximately 1. 6-fold greater than after a single dose. Absorption — After single oral-dose administration, the maximum observed plasma concentration (Cmax) of tadalafil is achieved between 30 minutes and 6 hours (median time of 2 hours) Distribution — The mean apparent volume of distribution following oral administration is approximately 63 L, indicating that tadalafil is distributed into tissues. At therapeutic concentrations, 94% of tadalafil in plasma is bound to proteins. Metabolism — Tadalafil is predominantly metabolized by CYP3A4 to a catechol metabolite. Excretion — The mean oral clearance for tadalafil is 2.5 L/hr and the mean terminal half-life is 17. 5 hours in healthy subjects. Tadalafil is excreted predominantly as metabolites, mainly in the feces (approximately 61% of the dose) and to a lesser extent in the urine (approximately 36% of the dose)

The pharmacokinetics of tadalafil are characterized by:

• Proportional increase in exposure with dose
• Steady-state plasma concentrations attained within 5 days
• Maximum plasma concentration achieved between 30 minutes and 6 hours
• Distribution into tissues with a mean apparent volume of distribution of approximately 63 L
• Metabolism by CYP3A4 to a catechol metabolite
• Excretion predominantly as metabolites in the feces (61% of the dose) and urine (36% of the dose)
• Mean terminal half-life of 17.5 hours in healthy subjects 2 2

From the Research

Pharmacokinetics of Tadalafil

• Tadalafil is distinguished from other phosphodiesterase type 5 (PDE5) inhibitors by its prolonged action, lasting 36 hours for a single dose 3.
• The pharmacokinetics of tadalafil are linear with respect to dose and duration of treatment, and a one-compartment model adequately describes the data 4.
• The absorption rate of tadalafil is rapid, with a typical population estimate of 1.86 h(-1) 4.
• The apparent oral clearance (CL/F) and apparent volume of distribution of tadalafil are 1.6 l/h and 63.8 l, respectively 4.
• Disposition parameters show a moderate degree of interindividual variability (39-45%) 4.
• Systemic exposure to tadalafil is not influenced by age, weight, smoking status, alcohol consumption, liver enzyme status, ED severity, cardiovascular condition, or diabetes mellitus 4.

Factors Affecting Pharmacokinetics

• The value of CL/F decreases slightly with increasing serum gamma-glutamyl transferase (GGT) concentration, which is the only statistically significant covariate detected 4.
• No patient-specific factor warranting clinical consideration of dose regimen adjustment was identified in the analyses 4.

Comparison with Other PDE5 Inhibitors

• Tadalafil demonstrates efficacy data approximately comparable to those of sildenafil and vardenafil 5.
• The pharmacokinetic profile of tadalafil allows for once-daily dosing, which is a convenient alternative to as-needed dosing 6.