Michaël Philippe (1,2), Michael Neely (3), Yves Bertrand (1), Nathalie Bleyzac (1,2), Sylvain Goutelle (2,4,5)
(1) Institute of Pediatric Hematology and Oncology, Lyon, France, (2) Laboratoire de Biométrie et Biologie Evolutive, UMR CNRS 5558, Université Lyon 1, Villeurbanne, France , (3) Laboratory of Applied Pharmacokinetics and Bioinformatics, Division of Pediatric Infectious Diseases, University of Southern California Children's Hospital Los Angeles, Los Angeles, USA, (4) Université Lyon 1, ISPB - Faculté de Pharmacie de Lyon, Lyon, France, (5) Service Pharmaceutique, Groupement Hospitalier de Gériatrie, Hospices Civils de Lyon, Lyon, France
Objectives: 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 [1]. This approach is theoretically ill-suited for targeting a range of exposure [2]. The objective of this work was to develop a general approach for optimal targeting of a drug exposure interval.
Methods: We used the nonparametric population pharmacokinetic (PK) model of IV busulfan (Bu) from Neely et al [3] to estimate the individual PK parameters of 163 bone marrow transplanted children (age= 6.1 ± 5.0 years old, IBW= 20.9 ± 13.9 kg) treated by IV Bu in Lyon (France). Then, an array of 151 doses of Bu ranging from 0.5 to 2 mg/kg was simulated a priori in each patient. For each dose, 29 possible Bu plasma concentration profiles, corresponding to the nonparametric prior, each associated with a probability, were obtained. The multiple-model (MM) -based, optimal dose was identified as that maximizing the a priori probability of achieving the Bu target AUC. Two AUC targets were considered: 900 – 1500 (conventional) or < 1500 µM.min-1. Finally, the MM optimal 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 [4,5,6], during a 4-day q.i.d. regimen of IV Bu.The Matlab software was used for all calculations.
Results: When targeting Bu conventional AUC range (900 – 1500 µM.min-1), the MM-dosing approach provided better attainment of than the best of the three other methods after one Bu dose, (82.2% versus 41.6%, p<0.005), two doses (79.1% versus 65.0%, p<0.005) and at the end of therapy, i.e. 16 doses (80.4% versus 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 MM approach was successful in minimizing overexposure as 0% of children showed simulated AUC > 1500 µM.min-1; while this percentage ranged from 0.6% to 4.3% for the other approaches.
Conclusions: A MM approach has been designed to optimize the targeting of an exposure interval. When applied to Bu in children, it outperformed the traditional model-based dosing approach, with earlier and better achievement of Bu target AUC. The approach can be applied for optimal dosing of many drugs, when the target objective is an interval.
References:
[1] Holford NH. Target concentration intervention: beyond Y2K. Br. J. Clin. Pharmacol. 2001;52 Suppl 1:55S – 59S
[2] D’Argenio DZ, Rodman JH. Targeting the systemic exposure of teniposide in the population and the individual using a stochastic therapeutic objective. J. Pharmacokinet. Biopharm. 1993;21:223–51.
[3] Neely M , et al. Accurately achieving target busulfan exposure in children and adolescents with very limited sampling and the BestDose software. To be published in Therapeutic Drug Monitoring 2016
[4] Nguyen L, et al. I.V. busulfan in pediatrics: a novel dosing to improve safety/efficacy for hematopoietic progenitor cell transplantation recipients. Bone Marrow Transplant. 2004;33:979–87.
[5] Paci A, et al. Pharmacokinetic behavior and appraisal of intravenous busulfan dosing in infants and older children: the results of a population pharmacokinetic study from a large pediatric cohort undergoing hematopoietic stem-cell transplantation. Ther. Drug Monit. 2012;34:198–208.
[6] McCune JS, et al. Busulfan in Infant to Adult Hematopoietic Cell Transplant Recipients: A Population Pharmacokinetic Model for Initial and Bayesian Dose Personalization. Clin. Cancer Res. 2014;20:754–63
Reference: PAGE 25 (2016) Abstr 5758 [www.page-meeting.org/?abstract=5758]
Poster: Methodology - New Modelling Approaches