Improved clinical outcome of paediatric bone marrow recipients using a test dose and Bayesian pharmacokinetic individualization of busulfan dosage regimens.
In order to control busulfan pharmacokinetic variability and toxicity, a specific monitoring protocol was instituted in our bone marrow transplant BMT paediatric patients including a test dose, daily Bayesian forecasting of busulfan plasma levels, and Bayesian individualization of busulfan dosage regimens. Twenty-nine children received BMT after a busulfan-based conditioning regimen. Individual pharmacokinetic parameters were obtained following a 0.5 mg*kg test dose and were used for daily individualization of dosage regimens during the subsequent 4-day course of treatment. Doses were adjusted to reach a target mean AUC per 6 h between 4 and 6 microg.h.ml(+1). Plasma busulfan assays were performed by liquid chromatography. Pharmacokinetic analysis used the USC*PACK software. The performance of the test dose to predict AUC during the busulfan regimen was evaluated. Incidence of toxicity, chimerism and relapse, overall Kaplan-Meier survival, and VOD-free survival were compared after matching our patients (group A) with patients conditioned by using standard doses of busulfan (group B). Busulfan doses were decreased in 69% of patients compared to conventional doses. Expected AUC was significantly correlated with observed AUC and predictability of the test dose was 101.9 +/- 17.9%. Incidence of VOD in group A was 3.4% vs 24.1% in group B, while the incidence of stomatitis was similar. Engraftment was successful in all patients in group A. The rate of full engraftment at 3 months post-BMT was higher in group A (P = 0.012). Long-term overall survival did not differ between the two groups, in contrast to the 90-day survival. VOD-free survival was higher in group A (P = 0.026). Pharmacokinetic monitoring and individualization of busulfan dosage regimen are useful in improving clinical outcome and reducing early mortality in paediatric bone marrow transplant recipients.
Bleyzac
N
N
Department of Pharmacy, Debrousse Hospital, Lyon, France.
Souillet
G
G
Magron
P
P
Janoly
A
A
Martin
P
P
Bertrand
Y
Y
Galambrun
C
C
Dai
Q
Q
Maire
P
P
Jelliffe
R W
RW
Aulagner
G
G
D000293:Adolescent; D000477:Alkylating Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001499:Bayes Theorem; D016026:Bone Marrow Transplantation / Q000009:adverse effects / Q000706:statistics & numerical data; D002066:Busulfan / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D002648:Child; D002675:Child, Preschool; D003520:Cyclophosphamide / Q000008:administration & dosage; D005047:Etoposide / Q000008:administration & dosage; D005260:Female; D030342:Genetic Diseases, Inborn / Q000628:therapy; D006085:Graft Survival; D019337:Hematologic Neoplasms / Q000628:therapy; D006504:Hepatic Veno-Occlusive Disease / Q000453:epidemiology / Q000209:etiology; D006801:Humans; D015994:Incidence; D007223:Infant; D015993:Life Tables; D008297:Male; D008558:Melphalan / Q000008:administration & dosage; D011446:Prospective Studies; D016511:Severe Combined Immunodeficiency / Q000628:therapy; D019172:Transplantation Conditioning / Q000009:adverse effects / Q000379:methods*; D014184:Transplantation, Homologous / Q000009:adverse effects; D016896:Treatment Outcome
D000477:Alkylating Agents; D005047:Etoposide; D003520:Cyclophosphamide; D002066:Busulfan; D008558:Melphalan