Population Pharmacokinetics of Lapatinib in Cancer Patients
Jianping Zhang, Kevin Koch
GlaxoSmithKline, Research Triangle Park, North Carolina, USA
Objectives: Lapatinib (TykerbTM) is a potent and selective inhibitor of the EGFR and HER2 tyrosine kinases. It is approved for the treatment of patients with advanced or metastatic breast cancer whose tumors overexpress HER2. This analysis was performed to describe the pharmacokinetic (PK) profile of lapatinib and to identify patient characteristics that influence lapatinib pharmacokinetics.
Methods: 27 patients from a Phase I study (dense data) and 263 patients from 3 Phase II studies (sparse data) contributed 2025 plasma lapatinib concentrations. Dosing in these studies varied from a single dose (SD) at 1500 mg to multiple doses at either 1500 mg daily (QD) or 500 mg twice daily (BID). For multiple dose studies, lapatinib concentrations were sampled on both Day 1 and Day 28. The population pharmacokinetic analysis was performed using a nonlinear mixed-effects modelling approach with NONMEM VI. Patient demographics, liver function, concomitant medications, and diarrhea scores were evaluated for their influence on lapatinib PK. The full covariate model was subject to backward elimination of insignificant or poorly estimated covariates. Visual predictive check was implemented for final model evaluation.
Results: Lapatinib PK was described by a two-compartment linear model with delayed zero-order and a first-order absorption functions. Mean (95% CI) parameter estimates were CL/F=40.2 (36.3, 44.1) L/hr, Vc/F=45.0 (33.7, 56.3) L, Q/F=10.9 (8.5, 13.4) L/hr, and Vp/F=338 (286, 390) L. Inter-individual variability in CL/F and Vc/F were 43% and 76%, respectively. Inter-occasion variability for CL/F between Days 1 and 28 was estimated to be 53%. CL/F was 42% lower (AUC 72% higher) with BID dosing. Bioavailability was 28% higher in Asian patients. Vc/F was 61% higher in Hispanic patients. Absorption rate (Ka) decreased with age. Drug induced diarrhea was not found to influence the lapatinib PK.
Conclusions: The population PK model developed in this analysis adequately characterized the pharmacokinetics of lapatinib which enabled identification and quantification of patient characteristics that influence lapatinib exposure. The model allows further analysis of relationship between lapatinib exposure and tumor response in patients with breast cancer.