A Nonparametric Method to Optimize Initial Drug Dosing and Attainment of a Target Exposure Interval: Concepts and Application to Busulfan in Pediatrics.

The traditional approach for model-based initial dosing is based on the use of a single vector of typical population parameters for targeting a specific exposure. This approach is theoretically ill-suited for targeting a range of exposure. The objective of this work was to develop a general approach for optimal (OPT) targeting of a drug exposure interval. After methodological purposes, we applied our method to the busulfan case. We used a nonparametric population pharmacokinetic model of intravenous busulfan to estimate the individual pharmacokinetic parameters of 163 bone marrow-transplanted children. Then, an array of 151 doses of busulfan ranging from 0.5 to 2 mg/kg was simulated a priori in each patient. For each dose, 29 possible busulfan plasma concentration profiles, corresponding to the nonparametric prior, each associated with a probability, were obtained. The multiple-model-based, OPT dose was identified as the dose maximizing the a priori probability of achieving the busulfan target area under the concentration-time curve (AUC). Two AUC targets were considered: 900-1500 (conventional) or <1500 µM min-1. Finally, the OPT dose was individually simulated in each patient. We compared the ability of this method to achieve the target exposure interval with that of three other traditional model-based methods and one based on the non-parametric approach. When targeting the busulfan conventional AUC range, the OPT dose provided better attainment than the best of the three other methods after one dose (82.2 vs. 41.7 %, p < 0.005), two doses (79.1 vs. 65.0 %, p < 0.005), and at the end of therapy (80.4 vs. 76.7 %, p < 0.42). The approach provided a balanced distribution between under- (10.4 %) and overexposure (9.2 %), while other approaches showed higher rates of underexposure (≥19 %). When targeting an AUC <1500 µM min, the OPT dose was successful in minimizing overexposure as 0 % of children showed simulated AUC >1500 µM min-1. Our approach has been designed to optimize the targeting of an exposure interval. When applied to busulfan in children, it outperformed the traditional model-based dosing approach, with earlier and better achievement of busulfan target AUC. The approach can be applied for OPT dosing of many drugs, when the target objective is an interval.