terval was eva luated in an open-label, single-arm study in patients with relapsed or refractory solid tumors. No large changes in the mean QTc interval (i.e., >20 ms) were detected in the study.
Pharmacokinetics
Absorption and Distribution
Following oral administration of Gilotrif tablets, time to peak afatinib plasma concentrations (Tmax) is 2 to 5 hours. Maximum concentration (Cmax) and area under the concentration-time curve from time zero to infinity (AUC0-∞) values increased slightly more than dose proportional in the range of 20 to 50 mg. The geometric mean relative bioavailability of 20 mg Gilotrif tablets was 92% as compared to an oral solution. In vitro binding of afatinib to human plasma proteins is approximately 95%.
A high-fat meal decreased Cmax by 50% and AUC0-∞ by 39% relative to the fasted condition [see Dosage and Administration (2.2)].
Metabolism and Elimination
Covalent adducts to proteins are the major circulating metabolites of afatinib and enzymatic metabolism of afatinib is minimal.
In humans, excretion of afatinib is primarily via the feces (85%) with 4% recovered in the urine following a single oral dose of [14C]-labeled afatinib solution. The parent compound accounted for 88% of the recovered dose.
The elimination half-life of afatinib is 37 hours after repeat dosing in cancer patients. Steady-state plasma concentrations are achieved within 8 days of repeat dosing of Gilotrif resulting in an accumulation of 2.8-fold for AUC and 2.1-fold for Cmax.
Specific Populations
Renal Impairment: The median trough afatinib plasma concentrations in patients with mild (CLcr 60-89 mL/min) and moderate (CLcr 30-59 mL/min) renal impairment were 27% and 85% higher than those in patients with normal renal function (CLcr ≥90 mL/min). Gilotrif has not been studied in patients with severely impaired renal function (CLcr <30 mL/min) [see Use in Specific Populations (8.7)].
Hepatic Impairment: Afatinib is eliminated mainly by biliary/fecal excretion. Mild (Child Pugh A) or moderate (Child Pugh B) hepatic impairment had no influence on the afatinib exposure following a single dose of Gilotrif. Subjects with severe (Child Pugh C) hepatic dysfunction have not been studied [see Use in Specific Populations (8.8)].
Body Weight, Gender, Age, and Race: Based on the population pharmacokinetic analysis, weight, gender, age, and race do not have a clinically important effect on exposure of afatinib.
Drug Interactions
Effect of P-gp Inhibitors and Inducers on Afatinib: The effect of ritonavir dosing time relative to a single oral dose of Gilotrif was eva luated in healthy subjects taking 40 mg of Gilotrif alone as compared to those after ritonavir (200 mg twice daily for 3 days) co-administration at 6 hours after Gilotrif administration. The relative bioavailability for AUC0-∞ and Cmax of afatinib was 119% and 104% when co-administered with ritonavir, and 111% and 105% when ritonavir was administered 6 hours after taking Gilotrif. In another study, when ritonavir (200 mg twice daily for 3 days) was administered 1 hour before a 20 mg single dose of Gilotrif, exposure to afatinib increased by 48% for AUC0-∞ and 39% for Cmax [see Drug Interactions (7)].
Pre-treatment with a potent inducer of P-gp, rifampicin (600 mg once daily for 7 days) decreased the plasma exposure to afatinib by 34% (AUC0-∞) and 22% (Cmax) [see Drug Interactions (7)].
P-glycoprotein (P-gp): Based on in vitro data, afatinib is a su |
