Population pharmacokinetic analysis resulting in a tool for dose individualization of busulphan in bone marrow transplantation recipients

The aims of the present study were (1) to investigate and quantify the phar macokinetics, including inter-occasion variability and covariate relationsh ips, of busulphan in BMT patients and (2) to develop a user-friendly initia l dosing and therapeutic drug monitoring (TDM) strategy for the treatment o f those patients with busulphan. The pharmacokinetics of busulphan was stud ied in 64 adults and 12 children who received busulphan (1 mg/kg) four time s daily for 4 days. A one-compartment model with first order absorption and a lag time was sufficient in describing the concentration-time profile. Or al clearance (CL/F) was found to be correlated to weight (+1.2%/kg), ALT (- 13%/mu cat/l) and concomitant phenytoin treatment (+21%). CL/F and the volu me of distribution (V/F) were estimated to 9.23 l/h and 39.3 1, respectivel y, in a typical individual. Inter-occasion variability (9.4%) in CL/F was e stimated to be less than inter-individual variability (28%), a prerequisite for the value of TDM. Bayesian CL/F estimates based on three samples were in good accordance with those based on all samples. The final population mo del was implemented into the program Excel. The resulting flexible and easy to use dosing program might be used for both initial and, requiring only t hree plasma samples, maintenance dose individualization of busulphan therap y.