Population pharmacokinetic and pharmacogenetic analysis of 6‐mercaptopurine in paediatric patients with acute lymphoblastic leukaemia
Authors: Hawwa Ahmed F. , Collier Paul S. , Millership Jeff S. , McCarthy Anthony , Dempsey Sid , Cairns Carole , McElnay James C. 
Published: August 2008

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• The cytotoxic effects of 6‐mercaptopurine (6‐MP) were found to be due to drug‐derived intracellular metabolites (mainly 6‐thioguanine nucleotides and to some extent 6‐methylmercaptopurine nucleotides) rather than the drug itself.

• Current empirical dosing methods for oral 6‐MP result in highly variable drug and metabolite concentrations and hence variability in treatment outcome.

WHAT THIS STUDY ADDS

• The first population pharmacokinetic model has been developed for 6‐MP active metabolites in paediatric patients with acute lymphoblastic leukaemia and the potential demographic and genetically controlled factors that could lead to interpatient pharmacokinetic variability among this population have been assessed.

• The model shows a large reduction in interindividual variability of pharmacokinetic parameters when body surface area and thiopurine methyltransferase polymorphism are incorporated into the model as covariates.

• The developed model offers a more rational dosing approach for 6‐MP than the traditional empirical method (based on body surface area) through combining it with pharmacogenetically guided dosing based on thiopurine methyltransferase genotype.

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.

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.

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.

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.