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

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Abstract

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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Acknowledgment

The authors would like to acknowledge Dr. Dennis Noe, Dr. Diane Mould, Dr. Marc R. Gastonguay, and Dr. Steve Riley for valuable discussions in the preparation of the manuscript, Dr. Michael Avery and Mr. David Wolford for the analytical assay of CP-724,714, and the patients and members of the Pfizer CP-724,714 team for their contributions to the Phase 1 study. The authors also would like to warmly thank Dr. Louis Denis for his contributions in the Phase 1 trial design and execution, and Dr. Pamela N. Munster, Dr. Carolyn D. Britten, Dr. Monica Mita, Dr. Karen Gelmon, Dr. Susan E. Minton, Dr. Stacy Moulder, Dr. Dennis J. Slamon, and Dr. Anthony W. Tolcher for conducting this Phase 1 trial.

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Authors and Affiliations

  1. Department of Clinical Pharmacology, Pfizer Global Research and Development, 50 Pequot Avenue MS6025-A3238, New London, CT, 06320, USA

    Feng Guo

  2. Department of Oncology, Pfizer Global Research and Development, 50 Pequot Avenue MS6025-A3119, New London, CT, 06320, USA

    Stephen P. Letrent

  3. Department of Clinical Pharmacology, Pfizer Global Research and Development, 50 Pequot Avenue MS6025-A3237, New London, CT, 06320, USA

    Amarnath Sharma

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  1. Feng Guo
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  2. Stephen P. Letrent
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Correspondence to Feng Guo.

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Guo, F., Letrent, S.P. & Sharma, A. Population pharmacokinetics of a HER2 tyrosine kinase inhibitor CP-724,714 in patients with advanced malignant HER2 positive solid tumors. Cancer Chemother Pharmacol 60, 799–809 (2007). https://doi.org/10.1007/s00280-007-0427-6

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  • DOI: https://doi.org/10.1007/s00280-007-0427-6

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