Pharmacokinetics of afatinib in subjects with mild or moderate hepatic impairment

Abstract

PurposeAfatinib, 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.MethodsThis 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 Cmax and AUC0–∞ between subjects with hepatic impairment and healthy matched controls. Study progression was based on drug-related toxicity (CTCAE v. 3.0) and Cmax of afatinib.ResultsAfatinib 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 AUC0–∞ was 92.6 % (90 % CI 68.0–126.3 %) and Cmax 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.ConclusionMild 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.

A highly efficient and sensitive LC‐MS/MS method for the determination of afatinib in human plasma: application to a metabolic stability study

“…The LOD and LOQ were 0.42 and 1.29 ng mL À1 , respectively; those values easily allow the determination of AFT in human plasma well below its reported C max values (Schnell et al, 2014;Stopfer et al, 2012;Wind et al, 2013). The proposed method was proven rugged and adequately sensitive for routine analysis of AFT.…”

“…AFT was produced by Boehringer-Ingelheim Pharmaceuticals Inc. (Ridgefield, CT, USA) and marketed with the trade name Gilotrif ® tablets (Afatinib dimaleate salt equivalent to 20, 30, and 40 mg afatinib base). In patients with mild or moderate hepatic impairment, the pharmacokinetic profiles and plasma protein binding of AFT were comparable to those in healthy subjects (Schnell et al, 2014). Investigations carried out on advanced solid tumor patients revealed that oral AFT has a good safety profile when administered alone (Gordon et al, 2013;Kristeleit et al, 2011;Marshall et al, 2013;Yap et al, 2010) or in combination with other cancer drugs.…”

“…1a} is a selective tyrosine kinase inhibitor, which indefinitely blocks the signaling pathways from the receptor tyrosine kinases EGFR/ErbB1, HER2/ErbB2 and ErbB4 (Schnell et al, 2014;Solca et al, 2012;Stopfer et al, 2012;Wind et al, 2013). Afatinib {AFT; (E)-N-[4-(3-chloro-4-fluoro-anilino)-7-[(3S)-tetrahydrofuran-3-yl]oxy-quinazolin-6-yl]-4-(dimethylamino)but-2-enamide; CAS 439081-18-2; Fig.…”

Epidermal growth factor receptor tyrosine kinase inhibitors in elderly patients with non-small cell lung cancer

“…These recommendations make no specific reference to age. However, in this era of polypharmacy, especially in the elderly population, a lack of metabolism by CYP3A4 is advantageous for patients treated with afatinib [47]. Since many of the commonly used medications are either CYP450 inhibitors or inducers, there is a smaller chance for drug-drug interactions in patients treated with afatinib, when compared to patients treated with gefitinib or erlotinib.…”

Efficacy of afatinib, an irreversible ErbB family blocker, in the treatment of intracerebral metastases of non-small cell lung cancer in mice

“…The lower IC 50 value indicates that afatinib is more potent than first-generation TKIs. Afatinib primarily binds to albumin in the plasma, and its binding ratio is more than 92% in mice and approximately 95% in humans [17][18][19] . Low albumin concentrations in the CSF contribute to unbound afatinib as the primary form.…”