Pharmacokinetic analysis of erlotinib and OSI-420 in pediatric patients with malignant gliomas

SCHAIQUEVICH P; PANETTA JC; THROM S; BAI F; BRONISCER A; STEWART CF

Orlando, USA

Congreso; American Society of Clinical Pharmacology and Therapeutics; 2008

 Background: To evaluate the population pharmacokinetics of erlotinib (ERL) and its metabolite OSI-420 in pediatric  patients with malignant gliomas enrolled on a Phase I study. Methods: Pharmacokinetic (PK) studies were obtained in 17 consenting patients studied at dosages of 70, 90, 120 or 160 mg/m2. Serial blood samples were obtained before and at 1, 2, 4, 8, 24, 30 and 48 hours after the first ERL dose and up to 24 h on day 8. Plasma ERL and OSI-420 concentrations were determined using a validated LC/MSMS method. Cmax, AUC0¨24, AUC0¨48, and Tmax after days 1 and 8 were calculated. The ratio of OSI-420 to ERL AUC0¨48 was calculated (REM). A population (PK) analysis was conducted to determine ERL apparent oral clearance (CLERL/F) and apparent volume of distribution (VERL/F), OSI-420 apparent elimination rate constant (keOSI-420/FF), and the absorption rate constant (ka). Inter- and intra-individual variability as well as inter-occasion variability was considered. A linear mixed effects model was implemented to explore the relationships among CYP3A4*1B, CYP3A5*3, MDR1 (exons 21 and 26) and BCRP (exons 2 and 5) SNPs and the PK parameters of ERL and OSI-420. Results: After the 1st and 8th ERL dose, the median Tmax ranged between 2 and 4 h. Neither Cmax nor AUC0¨48 showed a proportional increase with the actual ERL dosage administered. The REM was approximately 8% for all dosages studied. The mean population estimates were ka 0.44 h-1, CLERL/F 3.5 L/h/m2, VERL/F 54.2 L/m2, and keOSI-420/FF 3.5 h-1, respectively. Dosage was significantly related to Cl ERL/F (p<0.01). A significant relationship was found between ka and MDR1 exon 26 (p<0.05) and between keOSI-420/FF and CYP3A4*1A/*1B polymorphisms (p<0.05). Conclusion: The results obtained at steady-state are consistent with previously published data in adults. However, no relationship was noted between ERL dosage and Cmax or AUC.