Population Pharmacokinetics of High-Dose Carboplatin in Children and Adults

Abstract

Although for conventional dosing of carboplatin, several strategies are available to individualize the dose based on renal function measurements, such approaches are still rare for high-dose regimens with autologous stem cell support. The purpose of this study was to investigate the influence of patient- and regimen-specific factors on the pharmacokinetics of carboplatin and to compare the performance of different dose individualization strategies (Calvert, Newell, Chatelut, flat dosing, dosing according to body surface area). A combined data set with 69 patients from five studies, including 13 pediatric patients, was subject to a population pharmacokinetic analysis using NONMEM. The covariate analysis revealed that carboplatin clearance after high-dose chemotherapy was highly related to creatinine clearance, body height, and infusion duration. After inclusion of these covariates, the population parameter variability of clearance decreased from 53% in the base model to 21% in the final model. We also developed an alternative model that related body weight, instead of height, to clearance by means of allometric scaling. An evaluation of the predictive performance of existing a priori dose individualization strategies revealed that flat dosing is appropriate for adult patients with normal renal function receiving a 1-hour infusion. For a long-term infusion schedule, a dose increase may be necessary. The existing dosing strategies performed poorly for the children in our data set. For this subpopulation, our allometric scaling model may be most appropriate. The two population pharmacokinetic models presented can be applied to estimate individual carboplatin clearance in high-dose chemotherapy based on body weight or height, infusion duration, and creatinine clearance. After prospective evaluation, our models may be suitable for dose adjustments.