Influence of Underlying Disease on Busulfan Disposition in Pediatric Bone Marrow Transplant Recipients: A Nonparametric Population Pharmacokinetic Study

Busulfan is an alkylating agent used in a conditioning regimen prior to bone marrow transplantation. Busulfan has a narrow therapeutic index, giving rise to major liver toxicity (veno-occlusive disease), and a wide interpatient and intrapatient pharmacokinetic variability. This report presents the results of a population pharmacokinetic analysis leading to models based on underlying diseases requiring bone marrow transplantation. One hundred children received oral busulfan-based conditioning regimens between March 1998 and February 2006. Busulfan pharmacokinetic parameter estimates (Ka, first order absorption rate constant; Vs, volume of distribution related to the body weight; and Cl/F, apparent clearance) were estimated by using the nonparametric adaptative grid (NPAG) algorithm in patients divided into four groups according to initial diagnosis: metabolic diseases, hemoglobinopathies, hematological malignancies, and immune deficiencies. Ka and Vs did no differ significantly in the four subgroups. Cl/F and areas under the plasma concentration curve were significantly different in the four groups. Cl/F was significantly higher in the hemoglobinopathies group (P = 0.002), with a mean value of 7.78 L · h−1, whereas the immune deficiencies group was characterized by the lowest Cl/F (3.59 L · h−1). Interindividual variability was shown by high interindividual parameter percent coefficients of variation (CV%) but, nevertheless, with less diversity in the population parameter distributions for Vs in the three subgroups-metabolic diseases, hemoglobinopathies, and malignant diseases-and in Cl/F for patients with hemoglobinopathies. The fit was good for busulfan concentration predictions based on Bayesian individual posterior values, with little bias and good precision. In comparison with the overall population, the only model of subgroup presenting a greater precision was patients with hemoglobinopathies (P = 0.002). Use of these more specific models of a given disease may well result in more accurate individualization of busulfan dose regimens, especially in very sparse blood sampling situations.