Pharmacokinetics of afatinib in subjects with mild or moderate hepatic impairment

• Published in: Cancer chemotherapy and pharmacology Vol. 74; no. 2; pp. 267 - 275
• Main Authors: Schnell, David, Buschke, Susanne, Fuchs, Holger, Gansser, Dietmar, Goeldner, Rainer-Georg, Uttenreuther-Fischer, Martina, Stopfer, Peter, Wind, Sven, Petersen-Sylla, Marc, Halabi, Atef, Koenen, Rüdiger
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.08.2014; Springer; Springer Nature B.V
• Subjects: Adolescent; Adult; Aged; Antineoplastic agents; Area Under Curve; Biological and medical sciences; Cancer Research; Case-Control Studies; Female; Follow-Up Studies; Gastroenterology. Liver. Pancreas. Abdomen; Humans; Liver Diseases - drug therapy; Liver Diseases - metabolism; Liver. Biliary tract. Portal circulation. Exocrine pancreas; Male; Maximum Tolerated Dose; Medical sciences; Medicine; Medicine & Public Health; Middle Aged; Oncology; Original; Original Article; Other diseases. Semiology; Pharmacology. Drug treatments; Pharmacology/Toxicology; Prognosis; Quinazolines - administration & dosage; Quinazolines - pharmacokinetics; Receptor, ErbB-2 - antagonists & inhibitors; Tissue Distribution; Young Adult; Human; Hepatic impairment; Afatinib; Pharmacokinetics; Tyrosine kinase inhibitor; Epidermal growth factor receptor (EGFR); Antineoplastic agent; Enzyme; Transferases; Enzyme inhibitor; Hepatic disease; Epidermal growth factor receptor; Liver failure; Growth factor receptor; Digestive diseases; Protein-tyrosine kinase
• ISSN: 0344-5704; 1432-0843
• DOI: 10.1007/s00280-014-2484-y

Purpose Afatinib, an oral irreversible ErbB family blocker, undergoes minimal metabolism by non-enzyme-catalysed adduct formation with proteins or nucleophilic small molecules and is predominantly non-renally excreted via the entero-hepatic system. This trial assessed whether mild or moderate hepatic impairment influences the pharmacokinetics of afatinib. Methods This was an open-label single-dose study. Pharmacokinetic parameters after afatinib 50 mg were investigated in subjects with mild ( n  = 8) or moderate ( n  = 8) hepatic impairment (Child-Pugh A and B) and healthy controls ( n  = 16) matched for age, weight and gender. Plasma and urine samples for pharmacokinetic assessment were collected before and up to 10 days after dosing. Additional blood samples were drawn to determine ex vivo plasma protein binding of afatinib. Primary endpoints were comparisons of afatinib C max and AUC 0 – ∞ between subjects with hepatic impairment and healthy matched controls. Study progression was based on drug-related toxicity (CTCAE v. 3.0) and C max of afatinib. Results Afatinib pharmacokinetic profiles and plasma protein binding were similar in subjects with impaired liver function and healthy controls. Compared with matched controls, the afatinib-adjusted geometric mean ratio for AUC 0 – ∞ was 92.6 % (90 % CI 68.0–126.3 %) and C max was 109.5 % (90 % CI 82.7–144.9 %) for subjects with mild hepatic impairment, and 94.9 % (90 % CI 72.3–124.5 %) and 126.9 % (90 % CI 86.0–187.2 %), respectively, for subjects with moderate hepatic impairment. For all parameters, the 90 % CI included 100 %. Afatinib was generally well tolerated with no serious adverse events reported. Conclusion Mild to moderate hepatic impairment had no clinically relevant effect on the pharmacokinetics of a single 50 mg dose of afatinib, implying that adjustments to the starting dose of afatinib are not considered necessary in this patient population.