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.