Optimal sampling and model-based dosing algorithm for busulfan in bone marrow transplantation patients.
C. Piana (1), F. A. Castro (2), V.L. Lanchote (2), B.P. Simões (3); O.E. Della Pasqua (1,4)
(1) Division of Pharmacology, Leiden Academic Center for Drug Research, The Netherlands; (2) Department of Toxicology, University of São Paulo, Brazil; (3) Division of Haematology, Hospital das Clínicas, University of São Paulo, Brazil; (4) Clinical Pharmacology Modelling & Simulation, GlaxoSmithKline, Stockley Park, UK
Objectives: Busulfan is an alkylating agent used as part of a conditioning regimen in patients undergoing bone marrow transplantation. Busulfan presents high inter- and intra-individual variability in pharmacokinetics and has a very narrow therapeutic window, which has been linked to several adverse events [1]. Currently used therapeutic monitoring protocols are therefore aimed at busulfan dose individualisation, but evidence of achieving target exposure is not warranted. The aim of the current investigation was to determine the optimal scheme for PK sampling and develop a model-based dosing algorithm for busulfan in bone marrow transplantation patients.
Methods: Clinical data (n=29) from an ongoing study were used in our analysis. An existing one-compartment model with first order absorption and elimination [2] was selected as basis for sampling optimization and subsequent evaluation of a suitable dosing algorithm. Internal and external model validation procedures were performed prior to optimisation steps using ED- optimality criterion in PopED. Clearance and volume of distribution were considered as parameters of interest. The final sampling scheme was selected based on the predicted AUC(0-6) deviation from target exposure range obtained in a variety of simulation scenarios.
Results: A one-compartment model with ideal body weight [IBW] and alanine transferase [ALT] as covariates on clearance was found to accurately describe busulfan exposure after oral administration. The use of a model-based dosing algorithm appears to ensure that patients achieve the expected target exposure. In addition, a sparse sampling scheme with five samples per patient (t = 0.5, 2.25, 3, 4 and 5 hours after dose) was found to be sufficient for the characterization of busulfan pharmacokinetics. In contrast to the current clinical protocol, which relies on a linear correlation between dose and body weight, our findings reveal the clinical implications of a nonlinear correlation between body size, liver function and drug elimination.
Conclusions: The reduction from 15 to 5 blood samples constitutes an important improvement in routine therapeutic drug monitoring. Moreover, the availability of a model-based dosing algorithm for dose individualisation that accounts for the effects of IBW and ALT levels on busulfan clearance, may contribute to considerable improvement in the safety and efficacy profile of patients undergoing treatment for bone marrow transplantation.
References:
[1] Nath CE, Earl JW, Pati N, Stephen K, Shaw PJ. Variability in the pharmacokinetics of intravenous busulfan given as a single daily dose to paediatric blood or marrow transplant recipients. Br J Clin Pharmacol. 2008 Jul;66(1):50-9.
[2] Sandstrom M, Karlsson MO, Ljungman P, Hassan Z, Jonsson EN, Nilsson C, Ringden O, Oberg G, A Bekassy A, Hassan M. Population pharmacokinetic analysis resulting in a tool for dose individualization of busulfan in bone marrow transplantation recipients. Bone Marrow Transplantation (2001) 28, 657-664.