Population pharmacokinetic (PK) analysis of gefitinib in pediatric cancer patients.

SCHAIQUEVICH P; PANETTA JC; THROM S; DAW NC; GEYER JR; FURMAN WL; STEWART CF

Chicago, USA

Congreso; American Society of Clinical Oncology; 2008

ASCO

Background: Gefitinib is an orally active inhibitor of the epidermal growth factor receptor (EGFR) tyrosine kinase. Neuroblastoma, rhabdomyosarcoma, osteosarcoma, and high-grade gliomas are known to express EGFR. Thus, three phase I studies evaluating gefitinib pharmacokinetics were conducted in children with recurrent/refractory solid tumors (COG ADVL0016 and SJZD1839) or brain tumors (PBTC007). Because of wide inter-individual variability in gefitinib disposition, the present study was conducted to describe the population PK of gefitinib and to assess the relationship between gefitinib disposition and patient covariates. Methods: Subjects received daily oral gefitinib ranging from 100 to 500 mg/m2 as single agent therapy for 8 to 10 days prior to PK evaluation. Multiple plasma samples were collected per subject and analyzed using a validated LC MS/MS assay. The data consisted of 73 subjects and 600 samples. Data were analyzed using NONMEM v5 to obtain gefitinib apparent oral clearance (CL/F), apparent volume of distribution (V/F), and the absorption rate constant (ka). Covariates investigated included demographic (age, body surface area [BSA]) and laboratory variables, concomitant drug therapy (dexamethasone, H2-receptor antagonist), and genetic polymorphisms in CYP3A4*1B, CYP3A5*3C, CYP3A5*6, ABCB1 (exon 21 and 26), and ABCG2 (exons 2 and 5). Results: Gefitinib pharmacokinetics were described by a one-compartment model with first-order absorption. BSA was a significant covariate (p<0.05). The mean population estimates were CL/F 17.8 L/h/m2, V/F 348 L/h/m2, ka 0.519 h-1. A significant relationship was found between CL/F and ABCB1 exon 21 (p<0.05) and ABCB1 exon 26 (p<0.05) polymorphisms. Specifically, CL/F was decreased in patients homozygous for exons 21 and 26 (36% and 20%, respectively) relative to wild-type and heterozygous. Conclusions: The results obtained are consistent with published data in adults. The relationship between gefitinib CL/F and ABCB1 genetic polymorphisms explained a significant amount of the interindividual variability in CL/F.