Limited Sampling Strategies Supporting Individualized Dose Adjustment of Intravenous Busulfan in Children and Young Adults

Abstract

Background: Therapeutic drug monitoring (TDM) for busulfan supports dose adjustment during conditioning for stem cell transplantation. The authors aimed to develop and validate limited sampling strategies (LSS) of 4–5 samples for a precise estimation of the area under concentration (AUC)-time curve of busulfan, in plasma as an alternative to an intensive sampling strategy (ISS) requiring 9–10 samples. Methods: ISS TDM data from 297 patients (≤18 years of age) were used. AUCLSS was calculated using the trapezoidal rule and multiple linear regression (MLR). Unlike more complex modeling methods, MLR does not require sophisticated software or advanced training of personnel. MLR coefficients were estimated in the development subset containing randomly selected 50% of the records and were then used to calculate the AUCLSS of the remaining records (the validation subset). The agreement between dose adjustment recommendations (DAR) based on ISS and LSS, in the validation subset, was evaluated by a Bland–Altman analysis. A DAR deviating from an ISS-based reference by <15% was deemed acceptable. Results: Twelve LSSs were acceptable. Sampling at 0, 120, 180, and 240 minutes after the start of the second infusion (LSS15) yielded the best performance, with DAR deviating from the reference by <10% for 95% of cases; the AUCLSS was determined as follows: AUCLSS = 74.7954 × C(0) + 81.8948 × C(120) + 38.1771 × C(180) + 138.1404 × C(240) + 54.1837. This LSS and LSS13 performed similarly well in an independent external validation. Conclusions: MLR-based estimates of AUCLSS provide DARs that deviate minimally from the reference. LSSs allow the reduction of patient discomfort, a ∼50% reduction of TDM-related workload for nursing staff and blood loss and a ∼25% reduction in laboratory workload. These benefits may encourage wider use of busulfan TDM, supporting safe and efficacious personalized dosing.

Limited Sampling Strategy Using End of Infusion and Six-Hour Concentrations Overestimates Intravenous Busulfan Clearance Compared With Standard Six-Point Sampling in Hematopoietic Stem Cell Transplant Patients

“…In theory, only peak and trough concentrations may be necessary for the AUC determination in a one-compartment model, using the trapezoidal method; however, unfortunately, this method may lead to inaccurate estimates in the case of Bu, because the drug has a very narrow therapeutic index. 10,11 Similarly, we found in the present study that the actual results differed from what was expected in theory. One reason could be that we assumed that at time 24 hours in the OD dosing, the AUC level would reach zero, which was not actually the case.…”

A Method for Evaluating Robustness of Limited Sampling Strategies—Exemplified by Serum Iohexol Clearance for Determination of Measured Glomerular Filtration Rate

“…However, with Bayesian estimates (BE) based on, for example, a population pharmacokinetic model or the use of a linear regression model, accurate estimates of pharmacokinetic parameters and AUC may be obtained by using a limited number of optimally timed samples [2]. Such limited sampling strategies (LSS) may reduce the number of samples and limit the length of the study visit to make AUC-targeted TDM clinically applicable [3].…”

External Evaluation of Population Pharmacokinetic Models of Busulfan in Chinese Adult Hematopoietic Stem Cell Transplantation Recipients

“…Dosage can be adjusted by comparing the current AUC or Css with the target values. LSS has the advantage of predicting AUC with 2-4 samples ( Huang et al, 2017 ; Teitelbaum et al, 2020 ). Recently, personalized dosing strategy based on population pharmacokinetic (pop PK) model coupled with Bayesian forecasting has become popular ( Chaivichacharn et al, 2020 ; Gil Candel et al, 2020 ).…”