Pharmacokinetics of Afatinib, a Selective Irreversible ErbB Family Blocker, in Patients with Advanced Solid Tumours

Afatinib is a potent, irreversible, ErbB family blocker in clinical development for the treatment of a variety of solid tumours. This study evaluated the pharmacokinetics of afatinib (10–100 mg once daily) in cancer patients. Data from 221 patients with advanced solid tumours in four phase I and one phase II trial were analysed using non-compartmental methods. Within each dose group, the shape of the geometric mean plasma concentration–time profiles after single and multiple doses were comparable. Maximum plasma concentration (C max) values were achieved 2–5 h after dosing and thereafter declined at least bi-exponentially. Steady-state plasma concentrations were attained within 8 days after the start of dosing. The geometric mean terminal elimination half-life at steady state was about 37 h. Repeated dosing resulted in a 2.77-fold accumulation based on the area under the plasma concentration–time curve (AUC), and 2.11-fold accumulation based on C max values. A slightly more than dose-proportional increase in afatinib exposure was observed. There was moderate intra-individual variability in afatinib trough concentration values (the geometric coefficient of variation (gCV) ranged from 22.2 to 67.5 %). The inter-patient variability in plasma concentrations was moderate to high (e.g. at the 40 mg dose, the gCVs ranged from 35.6 to 221 %). The exposure to afatinib (as measured by AUC and C max) correlated with the severity of the most common adverse events of afatinib—diarrhoea and rash. The pharmacokinetic profile of afatinib supports a once-daily dosage regimen. As expected for this patient population, the pharmacokinetic parameters of afatinib showed moderate to high inter-patient variability. Afatinib exhibits non-linear pharmacokinetics.