Population PK/PD analysis of DX-8951F when administered to cancer patients

Background/Aim To evaluate DX-8951f by population pharmacokinetics (PPK). Methods Plasma and urine data were simultaneously modeled using PPK analyses (IT2S® and NONMEM®). Design Six non-comparative dose-escalation studies were included. Setting Patients were treated at hospitals. Participants 153 Intervention Dosing regimens varied from 30-minute infusions to 21-day continuous infusions at varying frequencies. Initial doses ranged from 0.05 to 4mg/m2. Results A linear 2-compartment PK model best described the plasma (n=2249) and urine (n=396) observations. Clinical covariates found to explain significantly the PK of DX-8951 were SGOT and calculated creatinine clearance on K10, gender on K10, K21, central volume of distribution (Vc) and fraction of dose excreted unchanged in urine (fe), body surface area on K10, K21 and Vc, bilirubin and CYP1A2 inhibitors on K10 and fe. Population estimates arising from NONMEM® and IT2S® were similar. The residual variability in plasma and urinary observations was low at 24.1% and 48.0%, respectively. Conclusions The PK of DX-8951 was found to be linear and well described by a simple 2-compartment model in this rich-sampling PPK analysis. Easily obtainable clinical covariates can be used to determine an adequate starting regimen of DX-8951. Clinical Pharmacology & Therapeutics (2005) 77, P93–P93; doi: 10.1016/j.clpt.2004.12.248