Pharmacokinetics of afatinib, a selective irreversible ErbB family blocker, in patients with advanced solid tumours

Clin Pharmacokinet. 2013 Dec;52(12):1101-9. doi: 10.1007/s40262-013-0091-4.


Background and objective: 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.

Methods: Data from 221 patients with advanced solid tumours in four phase I and one phase II trial were analysed using non-compartmental methods.

Results: 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.

Conclusion: 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.

Publication types

  • Clinical Trial, Phase I
  • Clinical Trial, Phase II
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Afatinib
  • Aged
  • Aged, 80 and over
  • Antineoplastic Agents / blood
  • Antineoplastic Agents / pharmacokinetics*
  • Female
  • Humans
  • Male
  • Middle Aged
  • Neoplasms / blood*
  • Protein Kinase Inhibitors / blood
  • Protein Kinase Inhibitors / pharmacokinetics*
  • Quinazolines / blood
  • Quinazolines / pharmacokinetics*
  • Receptor, ErbB-2 / antagonists & inhibitors*
  • Young Adult


  • Antineoplastic Agents
  • Protein Kinase Inhibitors
  • Quinazolines
  • Afatinib
  • ERBB2 protein, human
  • Receptor, ErbB-2