Back to Search
Start Over
Population pharmacokinetic and pharmacogenetic analysis of 6-mercaptopurine in paediatric patients with acute lymphoblastic leukaemia.
- Source :
-
British journal of clinical pharmacology [Br J Clin Pharmacol] 2008 Dec; Vol. 66 (6), pp. 826-37. Date of Electronic Publication: 2008 Sep 23. - Publication Year :
- 2008
-
Abstract
- Aims: To investigate the population pharmacokinetics of 6-mercaptopurine (6-MP) active metabolites in paediatric patients with acute lymphoblastic leukaemia (ALL) and examine the effects of various genetic polymorphisms on the disposition of these metabolites.<br />Methods: Data were collected prospectively from 19 paediatric patients with ALL (n = 75 samples, 150 concentrations) who received 6-MP maintenance chemotherapy (titrated to a target dose of 75 mg m(-2) day(-1)). All patients were genotyped for polymorphisms in three enzymes involved in 6-MP metabolism. Population pharmacokinetic analysis was performed with the nonlinear mixed effects modelling program (nonmem) to determine the population mean parameter estimate of clearance for the active metabolites.<br />Results: The developed model revealed considerable interindividual variability (IIV) in the clearance of 6-MP active metabolites [6-thioguanine nucleotides (6-TGNs) and 6-methylmercaptopurine nucleotides (6-mMPNs)]. Body surface area explained a significant part of 6-TGNs clearance IIV when incorporated in the model (IIV reduced from 69.9 to 29.3%). The most influential covariate examined, however, was thiopurine methyltransferase (TPMT) genotype, which resulted in the greatest reduction in the model's objective function (P < 0.005) when incorporated as a covariate affecting the fractional metabolic transformation of 6-MP into 6-TGNs. The other genetic covariates tested were not statistically significant and therefore were not included in the final model.<br />Conclusions: The developed pharmacokinetic model (if successful at external validation) would offer a more rational dosing approach for 6-MP than the traditional empirical method since it combines the current practice of using body surface area in 6-MP dosing with a pharmacogenetically guided dosing based on TPMT genotype.
- Subjects :
- Adolescent
Antimetabolites, Antineoplastic administration & dosage
Antineoplastic Combined Chemotherapy Protocols administration & dosage
Child
Child, Preschool
Dose-Response Relationship, Drug
Drug Administration Schedule
Female
Genotype
Humans
Male
Mercaptopurine administration & dosage
Mercaptopurine pharmacokinetics
Metabolic Clearance Rate genetics
Methyltransferases administration & dosage
Models, Biological
Pharmacogenetics
Precursor Cell Lymphoblastic Leukemia-Lymphoma genetics
Prospective Studies
Antimetabolites, Antineoplastic pharmacokinetics
Antineoplastic Combined Chemotherapy Protocols pharmacokinetics
Mercaptopurine analogs & derivatives
Methyltransferases pharmacokinetics
Precursor Cell Lymphoblastic Leukemia-Lymphoma drug therapy
Subjects
Details
- Language :
- English
- ISSN :
- 1365-2125
- Volume :
- 66
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- British journal of clinical pharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 18823306
- Full Text :
- https://doi.org/10.1111/j.1365-2125.2008.03281.x