Lapatinib Pharmacokinetics in Pediatric Patients with Recurrent or Refractory CNS Tumors

SCHAIQUEVICH P; PANETTA JC; FOULADI M; BAI F; FRAGA C; STEWART CF

San Diego CA, USA

Congreso; American Association of Pharmaceutical Sciences; 2007

AAPS

Purpose.  To characterize lapatinib pharmacokinetics in pediatric patients with recurrent or refractory CNS tumors and to assess the effect of dexamethasone.  Methods.  Lapatinib was administered orally twice daily (dosages: 300-1150 mg/m2/dose), and serial plasma samples (0, 0.5, 1, 1.5, 2, 4, 6, and 8 h) were obtained day 1 of courses 1 and 2. Lapatinib plasma concentrations were measured with a validated LC MS/MS method, and a one-compartment model with a lag time was fit to concentration-time data from 34 patients using a combination of maximum-likelihood (ML) and maximum a posteriori (MAP) Bayesian estimation (ADAPT II).  Specifically, the ML parameters for 40 of 52 studies were used in the subsequent Bayesian estimation to generate parameters for all patients. Pharmacokinetic parameters estimated included lag time (Tlag), absorption rate constant (ka), elimination rate constant (ke), and apparent volume of distribution (Vc/F).  Apparent oral clearance (CL/F) and area under the concentration-time curve to 12 h (AUC0-12) were calculated from the primary parameters.  Results.  Lapatinib maximum concentration occurred on average 3 to 4 h after the dose. The lapatinib AUC0-12 was related linearly to the BSA-normalized dosage administered during course 2 (r2 = 0.34, p<0.05) but not during course 1. No apparent relationship was observed between clearance and the actual dosage received in either course. A delay in lapatinib absorption was observed with a median lag time of 0.5-0.6 h. Using the MAP-Bayesian estimation criteria, the median values (range) for ke, Vc/F, ka, and CL/F for course 1 were: 0.21 h-1 (0.07-0.95), 67.4 L/m2 (32.5-277.4), 0.26 h-1 (0.04-1.5), and 18.3 L/h/m2 (4.6-103.8), respectively; and for course 2 were: 0.17 h-1 (0.06-0.4), 65.6 L/m2 (22.8-173.8), 0.19 h-1 (0.07-1.8), and 11.3 L/h/m2 (5.8-27.5), respectively. Using linear-mixed effects modeling, dexamethasone coadministration and course 2 were significantly associated with a decreased lapatinib clearance (p< 0.005, F-test).  Conclusion.  In this first report of lapatinib pharmacokinetics in pediatric cancer patients, we showed that dexamethasone coadministrtion and course of therapy were significantly associated with lapatinib disposition. Supported by USPHS Grants CA21765, CA81457, the Pediatric Brain Tumor Consortium, and ALSAC.