Purpose: The aim of this study is to determine the population pharmacokinetics of oral busulfan in Japanese adults.
Methods: We previously underwent a clinical trial involving the dose adjustment of oral busulfan depending on the individual pharmacokinetics using a test dose in hematopoietic stem cell transplantation recipients. Seventy-one Japanese patients aged from 16 to 67 years were enrolled. After taking oral busulfan 0.5 mg/kg as a test dose, blood samples were collected at five time points from each patient. Busulfan concentrations were measured by high-performance liquid chromatography, and the individual parameters were estimated by using the nonlinear mixed effects model computer program. A one-compartment model with first-order absorption was sufficient to describe the concentration-time profile.
Results: The final pharmacokinetic parameter were the clearance (CL/F) = 0.153 L/h/kg, distribution volume (Vd/F) = 0.695 L/kg, and absorption rate constant (ka) = 2.39 h(-1). The inter-individual variabilities in CL/F, Vd/F and ka were 25.9, 26.2, and 111.8%, respectively, and the residual variability was 12.1% as the coefficient of variation.
Conclusion: We developed a population pharmacokinetic model of oral busulfan in Japanese adults. The final population model was implemented into the program excel, leading to an easy and proper therapeutic monitoring of oral BU by using small number of samples.