Development of a Population Pharmacokinetic Model of Busulfan in Children and Evaluation of Different Sampling Schedules for Precision Dosing

Abstract

We develop a population pharmacokinetic model to describe Busulfan pharmacokinetics in paediatric patients and investigate by simulations the impact of various sampling schedules on the calculation of AUC. Seventy-six children had 2 h infusions every 6 h. A two-compartment linear model was found to adequately describe the data. A lag-time was introduced to account for the delay of the administration of the drug through the infusion pump. The mean values of clearance, central volume of distribution, intercompartmental clearance, and peripheral volume of distribution were 10.7 L/h, 39.5 L, 4.68 L/h and 17.5 L, respectively, normalized for a Body Weight (BW) of 70 kg. BW was found to explain a portion of variability with an allometric relationship and fixed exponents of 0.75 on clearance parameters and 1 on volumes. Interindividual variability for clearance and volume of distribution was found to be 28% and 41%, respectively, and interoccasion variability for clearance was found to be 11%. Three sampling schedules were assessed by simulations for bias and imprecision to calculate AUC by a non-compartmental and a model-based method. The latter was found to be superior in all cases, while the non-compartmental was unbiased only in sampling up to 12 h corresponding to a once-daily dosing regimen.

Population Pharmacokinetics of Busulfan and Its Metabolite Sulfolane in Patients with Myelofibrosis Undergoing Hematopoietic Stem Cell Transplantation

“…Our data suggests that the pharmacokinetics of busulfan and its metabolite sulfolane are best described by a one-compartment model with first-order elimination. This lies in accordance with most of the published PK analyses of busulfan, even though there are few two-compartmental models for busulfan reported as well [13,26,39,40]. Most published PopPK models of busulfan set the focus either on pediatric patients as the IIV as well as the IOV of busulfan PK in children and young adults are even more difficult to predict [20,21] or on large study populations including various malignancies [11,13].…”

Precision Oncology by Point-of-Care Therapeutic Drug Monitoring and Dosage Adjustment of Conventional Cytotoxic Chemotherapies: A Perspective

“…However, actual practices still differ between TDM centers. Additionally, a two-compartmental model has been demonstrated to improve the accuracy of AUC calculations towards dosage adjustments [35].…”

In Silico Pharmacology for Evidence-Based and Precision Medicine

“…For instance, the utilization of PK models can sufficiently predict PK profiles of drugs with narrow therapeutic indexes and/or of high intra- or inter- subject variability in general or in special population groups. For example, through pharmacometrics approaches, the PK profile of busulfan administration in paediatric patients undergoing hematopoietic stem cell transplantation (HSCT) can be utilized for an optimum dosing regimen [ 10 ]. In addition, even for drugs marketed for a long time (i.e., nebivolol), population–PK model approaches can provide important information through the M&S of different scenarios such as the impact of age or genotype characteristics on optimum dose selection regarding drugs’ efficacy and safety [ 11 ].…”