Using pharmacokinetic and pharmacodynamic modeling and simulation to evaluate importance of schedule in topotecan therapy for pediatric neuroblastoma

JOHN C PANETTA; PAULA SCHAIQUEVICH; VICTOR M SANTANA; CLINTON F STEWART

CLINICAL CANCER RESEARCH

American Association for Cancer Research

Año: 2008 vol. 14 p. 318 - 325

1557-3265

Purpose: The study aims to use mathematical modeling and simulation to assess the relativecontribution of topotecan systemic exposure and scheduling in the activity and myelosuppres-sion of topotecan in pediatric patients with neuroblastoma.Experimental Design: Pharmacokinetic and pharmacodynamic data were obtained from aphase II study for pediatric patients with high-risk neuroblastoma. The topotecan dosage wasindividualized to attain a topotecan lactone area under the plasma concentration-time curvebetween 80 and 120 ng/mL h and given over a protracted schedule (i.e., 10 days). Four mathe-maticalmodels describing topotecan pharmacokinetics, tumor growth, and neutrophil and plate-let dynamics were developed. The models were combined to simulate and compare differenttopotecan treatment strategies with respect to systemic exposure and schedule.Results: The median change in tumor volume was significantly different between schedules(5% increase for D 5 versus 60% decrease for D 5 2; P < 0.0001) when administeringthe same total systemic exposure.Whereas protracted schedules showed increased neutropenia(median of 7 versus 12 days below an absolute neutrophil count of 500/AL; P < 0.0001)and thrombocytopenia (median of 3 versus 10 days below a platelet count of 20,000/AL;P < 0.00001), simulations showed that delays in topotecan therapy would not be required.Simulations showed that an increase in topotecan exposure on the D 5scheduleby2.4-foldresulted in a modest decrease in tumor volume (i.e., median percentage change tumor volumeof 24% versus 3%).Conclusions: The present mathematical model gave an innovative approach to determiningrelevant topotecan schedules for possible evaluation in the clinic, which could lead to improvedtumor response withminimized toxicities.