Cialis Pharmacokinetics (ADME): How Tadalafil Is Absorbed, Distributed, Metabolized, and Eliminated

How fast is tadalafil absorbed?

After an oral dose, tadalafil reaches peak plasma concentration somewhere between 30 minutes and 6 hours, with a median of 2 hours [1]. In a pooled analysis of 13 clinical pharmacology studies covering 237 healthy subjects, mean peak concentration after a 20 mg dose was 378 micrograms per liter at 2 hours, and exposure rose in proportion to dose, so doubling the dose doubled exposure [2].

Food does not change absorption in any meaningful way. The Cialis label says the tablet may be taken with or without food [1], and the pooled healthy-volunteer data found food had negligible effects on bioavailability, judged by 90% confidence intervals for peak-concentration and total-exposure ratios [2]. An antacid containing magnesium hydroxide and aluminum hydroxide taken at the same time slowed the apparent rate of absorption without changing total exposure, and the H2 blocker nizatidine had no significant effect [1].

The 30-minute to 6-hour window describes time to peak blood concentration, not how long the effect lasts [1].

What happens to tadalafil once it is in the blood?

Tadalafil distributes into an apparent volume of distribution of about 63 L; the pooled healthy-volunteer estimate was 62.6 L, with a 5th to 95th percentile range of 39.5 to 92.1 L [1][2]. It is 94% bound to plasma protein [1]. Less than 0.0005% of a dose appears in semen [1].

Body size, age, sex and smoking did not produce clinically meaningful changes in exposure in the 237-subject pooled analysis [2]. A population model built from 227 men with erectile dysfunction in a phase 3 trial found exposure was not influenced by age, weight, smoking status, alcohol consumption, liver enzyme status, ED severity, cardiovascular condition or diabetes [3]. The one covariate that reached significance in that model was gamma-glutamyl transferase, with clearance falling slightly as GGT rose [3].

How is tadalafil metabolized?

Tadalafil is metabolized mainly by CYP3A4 to a catechol metabolite, and the metabolites are not expected to be pharmacologically active [1]. Mean oral clearance is about 2.5 L/h (2.48 L/h, 5th to 95th percentile 1.35 to 4.35) [1][2].

Some drugs that affect CYP3A4 substantially change tadalafil exposure; the measured effects and the label's predictions differ by drug [1].

• Ketoconazole 400 mg daily raised tadalafil 20 mg exposure (AUC) by 312% and peak concentration by 22%; ketoconazole 200 mg daily raised tadalafil 10 mg AUC by 107% and peak by 15% [1].
• Ritonavir 200 mg twice daily raised tadalafil 20 mg AUC by 124% with no change in peak concentration. The higher 500 to 600 mg twice-daily regimen raised AUC by only 32% and lowered peak concentration by 30%, because ritonavir also induces enzymes [1].
• Erythromycin, itraconazole and grapefruit juice were not studied with tadalafil, but the label states they would likely increase exposure [1].

With a potent CYP3A4 inhibitor, the Cialis label caps as-needed dosing at 10 mg no more often than every 72 hours, and once-daily dosing at 2.5 mg [1].

In the other direction, rifampin 600 mg daily cut tadalafil 10 mg AUC by 88% and peak concentration by 46% [1]. Carbamazepine, phenytoin and phenobarbital would likely lower exposure but were not studied [1]. The label calls for no dose adjustment with inducers, while noting that the reduced exposure can be anticipated to decrease the efficacy of once-daily Cialis by an unknown amount [1].

How is tadalafil eliminated, and why does the half-life matter?

Tadalafil leaves the body as metabolites: about 61% of a dose in feces and 36% in urine [1]. The mean terminal half-life is 17.5 hours in healthy subjects, with a 5th to 95th percentile range of 11.5 to 29.6 hours [2]; the label gives 17.5 hours [1].

The up-to-36-hour figure is not a 36-hour erection. The label says Cialis improved erectile function compared with placebo for up to 36 hours after a dose, and that sexual stimulation is still required [1]. Sildenafil's half-life is about 4 hours by comparison [1].

Nitrates are contraindicated with Cialis. In a crossover study of 150 men who took tadalafil 20 mg or placebo daily for 7 days and then sublingual nitroglycerin 0.4 mg, more men on tadalafil had standing systolic blood pressure fall below 85 mm Hg at 4, 8 and 24 hours, with no difference at 48, 72 and 96 hours [4]. The label says that at 48 hours a few more tadalafil men still had greater blood pressure falls [1]. For a life-threatening situation where a nitrate is medically necessary, the label says at least 48 hours should pass after the last Cialis dose before a nitrate is considered, and then only under close medical supervision with hemodynamic monitoring [1].

Does once-daily Cialis reach steady state?

Steady state is reached by day 5 of once-daily dosing, and exposure at steady state is about 1.6-fold that of a single dose, consistent with the half-life [1][2]. The label notes that once-daily Cialis provides continuous plasma tadalafil levels and that this should be considered when evaluating interactions with nitrates, alpha-blockers, antihypertensives and potent CYP3A4 inhibitors [1].

What changes exposure: kidneys, liver, age

Kidneys. Exposure (AUC) is about doubled in mild (creatinine clearance 51 to 80 mL/min) or moderate (31 to 50 mL/min) renal impairment after single 5 to 10 mg doses [1]. For as-needed use with creatinine clearance 30 to 50 mL/min, the label recommends starting at 5 mg with a maximum of 10 mg no more often than every 48 hours; below 30 mL/min or on hemodialysis, the as-needed maximum is 5 mg, taken no more often than once every 72 hours, and once-daily use is not recommended [1].

Liver. For as-needed use in mild or moderate impairment (Child-Pugh A or B), the dose should not exceed 10 mg once daily; in severe impairment (Child-Pugh C), Cialis is not recommended [1].

Age. Exposure is 25% higher in healthy men aged 65 or older [1], although the pooled analysis of healthy volunteers found no clinically meaningful age effect [2].

Does tadalafil change the levels of other drugs?

Rarely. Tadalafil does not inhibit or induce CYP1A2, CYP3A4, CYP2C9, CYP2C19, CYP2D6 or CYP2E1 [1]. It did not change warfarin exposure or prothrombin time, did not potentiate aspirin's effect on bleeding time, did not change midazolam or lovastatin exposure, and did not alter digoxin steady state; with theophylline it added a heart-rate rise of about 3 beats per minute [1]. Alcohol and tadalafil do not change each other's plasma concentrations, although the label warns that 5 or more units of alcohol with Cialis can increase orthostatic signs and symptoms [1].

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