1. ¹Institut de Recherche Pierre Fabre, Castres, France
2. ²Orphan Medical Inc., Minnetonka, USA

Correspondence: Dr L Nguyen, Clinical Pharmacokinetic Department, Institut de Recherche Pierre Fabre, 11 rue Théron Périé, 81106 Castres Cedex, France. E-mail: laurent.nguyen@pierre-fabre.com

Received 19 September 2003; Accepted 1 December 2003; Published online 5 April 2004.

Abstract

A retrospective population pharmacokinetic (PPK) analysis was performed in 24 pediatric patients (PEDS) (0.45–16.7 years old) receiving i.v. busulfan/cyclophosphamide (i.v. Bu/Cy 4) regimen prior to allogeneic hematopoietic stem cell transplantation. I.V. Bu doses were given as a 2-hour infusion every 6 h over 4 days. Initial dosing of i.v. Bu was 1 mg/kg for children 4 years old and 0.8 mg/kg for patients >4 years old. Bu plasma concentrations at doses 1, 9 and 13 were analyzed through a multivariate NONMEM analysis. A close log-linear relationship between body weight (BW) and i.v. Bu clearance was demonstrated with no further age-dependency or gender effect. The interpatient coefficient of variation (CV) in Bu clearance significantly decreased from 56% (covariate-free model) to 19% (BW covariate model) and reproducible i.v. Bu exposure between doses was illustrated (intraindividual CV=9%). Based on the PPK model, a novel Bu dosing regimen (ie: doses in mg/kg adjusted to discrete weight categories) for a better AUC targeting was developed by simulation on 1000 patients. Age-based dosing was demonstrated not to be clinically relevant with i.v. Bu. Use of the new BW-based dosing appears to be more appropriate for the PEDS.