翠-ChallengesofPharmacokineticPharmacodynamic.pptVIP

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翠-ChallengesofPharmacokineticPharmacodynamic.ppt

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翠-ChallengesofPharmacokineticPharmacodynamic.ppt

Challenges of Pharmacokinetic/Pharmacodynamic Assessments in Pediatric Oncology Outline Summary of results of early clinical pharmacokinetic studies with topoisomerase I inhibitors Application of results from nonclinical studies of topoisomerase I inhibitors to design of clinical trials (Phase Ib/IIa) Summary results of later clinical drug development with topoisomerase I inhibitors (Phase Ib/Phase IIa) Thoughts regarding design of clinical pharmacokinetic studies of “targeted” drug therapy Pharmacology Studies EnhanceDevelopment of Anticancer Drugs Two Commercially Available Topoisomerase I Inhibitors For Use In Pediatric Oncology:Topotecan and Irinotecan Initial Clinical Trials with Topoisomerase I Inhibitors in Children with Cancer Topotecan 72-hour CI in children with recurrent solid tumors (Pratt, JCO, 1994) Antitumor activity* DLT myelosuppression Preliminary data for LSM Initial Clinical Trials with Topoisomerase I Inhibitors in Children with Cancer Oral topotecan (15 or 21-days) in children with refractory solid tumors (Zamboni, CCP, 1999) Well absorbed Wide interpatient variability but less than intrapatient Initial Clinical Trials with Topoisomerase I Inhibitors in Children with Cancer Topotecan 30-min infusion (dx5) in children with recurrent solid tumors (POG-9275; Tubergen, Stewart JPHO, 1996) Antitumor activity DLT myelosuppression Validation of LSM Wide interpatient variabilityin clearance with small (~20%) dosage increments, overlap in topotecan exposure across dose levels Initial Clinical Trials with Topoisomerase I Inhibitors in Children with Cancer Irinotecan 60-min infusion (dx5x2) in children with recurrent solid tumors (Furman, JCO, 1999) Antitumor activity DLT diarrhea Pharmacokinetics complex with metabolism to active (SN-38) and inactive metabolites SN-38 highly protein bound Role for pharmacogenetics Comparison of Results from Adult and Pediatric Phase I Studies for the Topoisomerase I Inhibitors Pharmacokinetics Topotecan lactone s