Population pharmacokinetics of temozolomide in cancer patients

Purpose. To evaluate covariate effects on the pharmacokinetics of temozolom ide in cancer patients, and to explore the dosepharmacokinetics-toxicity re lationship of temozolomide. Methods. Non-Linear mixed-effects modeling approach was used to analyze the data from 445 patients enrolled in eleven Phase I and Phase II clinical tr ials. All patients in the phase I trials had advanced cancer. Patients in t he phase II trials had anaplastic astraocytoma IAA), glioblastoma multiform e (GBM) or malignant melanoma (MM). A sparse sampling scheme was prospectiv ely developed using Phase I data and was successfully implemented in Phase II trials. Population factors included age, gender, height (HT), weight (WT ), body surface area (BSA), serum creatinine (Sr.Cr.), estimated creatinine clearance, serum chemistry data as indices of hepatic function and disease , smoking status, and selected concomitant medications. Descriptive statist ics were used to summarize the toxicity and temozolomide dose and exposure relationship. Results. The pharmacokinetics of temozolomide fellows a one-compartment mod el with first order absorption and elimination. Temozolomide clearance (CL) increased with BSA for both genders. The population mean clearance for GEM or AA patients was 11.2 L/hr for male with BSA equal to 2.0 m(2), and 8.8 L/hr for female with BSA. equal to 1.7 m(2). The mean clearance for MM pati ents was slightly higher. The inter-subject variability in clearance was 15 %, and the residual variability was 26%. Other factors investigated in this analysis had Little effect an clearance. The overall incidence of neutrope nia and thrombocytopenia were 5-8%. Temozolomide dose and AUC did not predi ct nadir neutrophil and platelet counts due to large variability in counts. Conclusions. The current dose regimen is administered according to BSA whic h is the most important factor influencing temozolomide clearance. No furth er dose adjustment is required.