Population pharmacokinetics of a HER2 tyrosine kinase inhibitor CP-724,714 in patients with advanced malignant HER2 positive solid tumors

Feb 8, 2007Cancer chemotherapy and pharmacology

How the body processes the HER2-targeting drug CP-724,714 in patients with advanced HER2-positive solid tumors

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Abstract

A 2-compartment pharmacokinetic model for CP-724,714 was developed using concentration-time data from 30 cancer patients.

Concentration-time data included 484 observations from patients receiving various dosing regimens of CP-724,714.
The model showed inter-subject variability in oral elimination clearance and volume of distribution.
Body weight was found to influence the clearance rate, reducing variability by approximately 20%.
No significant effects of age, race, or liver metastasis on the drug's disposition were observed.
The pharmacokinetic model can be used to simulate future clinical trials for CP-724,714.

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PURPOSE: To develop a population pharmacokinetic (popPK) model for CP-724,714, a novel HER2 tyrosine kinase inhibitor is under development for the treatment of advanced HER2 positive cancers.

METHODS: Concentration-time data (n = 484) from 30 cancer patients receiving daily oral CP-724,714 at doses of 250 mg QD, 250 mg BID, 250 mg TID, and 400 mg BID in 21-day cycles in an open label First-in-Human dose-escalation study were evaluated. Serum concentrations of CP-724,714 were obtained after single dose and at steady state. Nonlinear mixed effect analysis in NONMEM using first order conditional estimation with interaction (FOCEI) was performed. The effect of covariates was assessed. Diagnostic plots, decrease of objective function value (>7.8), bootstrapping, and predictive check were used as model selection criteria.

RESULTS: A 2-compartment first-order absorption pharmacokinetic (PK) model with inter-subject variability (ISV) on the apparent oral elimination clearance (CL/F), apparent central volume of distribution (V1/F), apparent peripheral volume of distribution (V2/F), and first-order oral absorption rate constant (ka), interoccasion variability (IOV) on CL/F, and body weight (WT) as covariate on CL/F was developed. There was no evidence of dose-dependent and/or time-dependent PK. CL/F increased with increasing WT. The ISV of CL/F was reduced by approximately 20% with WT as a covariate. Age, race, and liver metastasis did not influence CP-724,714 disposition.

CONCLUSIONS: A popPK model was developed that adequately described the pharmacokinetics of CP-724,714. WT was identified as a covariate on CL/F that reduced ISV and improved model performance. Future studies will further assess the importance of WT as a pharmacokinetic covariate. The proposed popPK model can be used to simulate CP-724,714 Phase 2/3 trials.

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Population pharmacokinetics of a HER2 tyrosine kinase inhibitor CP-724,714 in patients with advanced malignant HER2 positive solid tumors

Abstract

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