PII‐70

BACKGROUND To conduct a population pharmacokinetic (PopPK) analysis for CP‐724714, a novel HER2 tyrosine kinase inhibitor under development for the treatment of advanced HER2 positive cancers. METHODS Concentration data (n=560) from 30 cancer patients receiving daily oral CP‐724714 in 21‐day cycles in an open label First‐in‐Human dose‐escalation study were used. Cohorts of 250 mg QD, 250 mg BID, 250 mg TID and 400 mg BID were evaluated. Serum levels of CP‐724714 were obtained after single dose and at steady state. Mixed effect analysis (FOCE) in NONMEM and bootstrapping were performed. The effect of covariates was assessed. Diagnostic plots, decrease of objective function value (≥10.83) and predictive check were used as model selection criteria. RESULTS A 2‐compartment 1st‐order absorption PK model with interpatient variability on CL/F and Vc/F, and BSA as covariate on CL/F and Vc/F was developed. Results revealed linear PK across the dose range evaluated. CL/F and Vc/F increased with increasing BSA. Interpatient variability of CL/F and Vc/F was reduced by ∼30% with BSA as a covariate, respectively. Age, gender, ethnicity, and LFTs did not influence CP‐724714 disposition. CONCLUSIONS The final PopPK model adequately described CP‐724714 PK profiles. BSA was identified as a covariate that reduced PK variability and improved model predictability. Future studies will further assess the importance of BSA as a PK covariate. The proposed PopPK model could be used to simulate CP‐724714 Phase 2 trials. Clinical Pharmacology & Therapeutics (2005) 79 , P54–P54; doi: 10.1016/j.clpt.2005.12.195