Pharmacokinetics and safety of erlotinib and its metabolite OSI-420 in infants and children with primary brain tumors

Purpose Erlotinib (Tarceva ® ), a potent small molecule inhibitor of the epidermal growth factor receptor tyrosine kinase, has been evaluated to treat infants and children with primary brain tumors. The pharmacokinetics of erlotinib and its primary metabolite OSI-420 were characterized and exposure–safety associations were investigated. Methods This analysis involved patients enrolled in two clinical studies and receiving oral erlotinib once daily as part of treatment. Single-dose and steady-state erlotinib and OSI-420 plasma concentrations were assayed using HPLC–MS/MS methods. Population pharmacokinetic modeling and univariate covariate analysis evaluating demographic, clinical and selected CYP3A5 , CYP3A4 , ABCB1 , and ABCG2 genotypes were performed. Associations between erlotinib and OSI-420 pharmacokinetics, and with toxicities (diarrhea and skin rash) occurring post-dose were explored. Results Data from 47 patients (0.7–19 years old) were collected and best fitted by one-compartment linear models. Erlotinib and OSI-420 apparent clearances (CL/ F and CL m / F m ) were higher in patients < 5 years compared to older patients (mean CL/ F : 6.8 vs 3.6 L/h/m 2 , and mean CL m / F m : 79 vs 38 L/h/m 2 , p < 0.001), and were 1.62-fold and 1.73-fold higher in males compared to females ( p < 0.01). Moreover, CL/ F was 1.53-fold higher in wild-type patients than in patients heterozygous or homozygous mutant for ABCG2 rs55930652 ( p < 0.05). Most of the toxicities reported were grade 1. No associations were found between drug pharmacokinetics and drug-induced toxicities. Conclusions Erlotinib therapy was well tolerated by pediatric patients with primary brain tumors. No dosing adjustments based on age or patient characteristics are recommended for this patient population.