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

• Published in: Clinical pharmacokinetics Vol. 52; no. 12; pp. 1101 - 1109
• Main Authors: Wind, Sven, Schmid, Marion, Erhardt, Julia, Goeldner, Rainer-Georg, Stopfer, Peter
• Format: Journal Article
• Language: English
• Published: Cham Springer International Publishing 01-12-2013; Adis International; Springer Nature B.V
• Subjects: Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Agents - blood; Antineoplastic Agents - pharmacokinetics; Biological and medical sciences; Female; General pharmacology; Humans; Internal Medicine; Male; Medical sciences; Medicine; Medicine & Public Health; Middle Aged; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); Neoplasms - blood; Original Research Article; Pharmacokinetics. Pharmacogenetics. Drug-receptor interactions; Pharmacology. Drug treatments; Pharmacology/Toxicology; Pharmacotherapy; Protein Kinase Inhibitors - blood; Protein Kinase Inhibitors - pharmacokinetics; Quinazolines - blood; Quinazolines - pharmacokinetics; Receptor, ErbB-2 - antagonists & inhibitors; Tumors; Young Adult; Disposition Phase; Power Model Regression; Advanced Solid Tumour; Electronic Supplementary Material; Dose Group; Antineoplastic agent; Human; Solid tumor; Afatinib; Tyrosine kinase inhibitor; Advanced stage; Malignant tumor; Antagonist; Irreversible; Pharmacokinetics; Cancer
• ISSN: 0312-5963; 1179-1926
• 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.