ArticleBritish journal of clinical pharmacology2015
Physiologically based pharmacokinetic model for 6-mercpatopurine: exploring the role of genetic polymorphism in TPMT enzyme activity.
Article in British journal of clinical pharmacology, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 6 papers, 1 of them a synthesis that pooled it.
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Who cites it
6 citing papers in PubMed, 1 synthesis or guideline pooled it, 22 citations in OpenAlex.
- Utility of physiologically based pharmacokinetic (PBPK) modeling in oncology drug development and its accuracy: a systematic review.European journal of clinical pharmacology · 2018Pooled it
- A Rapid and Reliable Absorbance Assay to Identify Drug-Drug Interactions with Thiopurine Drugs.Metabolites · 2024Article
- Genome-Wide Association Study for the Genetic Determinants of Thiopurine Methyltransferase Protein Expression in Human Livers and Racial Differences.Pharmaceutical research · 2023Article
- Precision therapy of 6-mercaptopurine in Chinese children with acute lymphoblastic leukaemia.British journal of clinical pharmacology · 2020Article
- Genotypes Affecting the Pharmacokinetics of Anticancer Drugs.Clinical pharmacokinetics · 2017Review
- Pharmacogenomics in Pediatric Oncology: Review of Gene-Drug Associations for Clinical Use.International journal of molecular sciences · 2016Review
Corrections and comments
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
Abstract
aimsTo extend the physiologically based pharmacokinetic (PBPK) model developed for 6-mercaptopurine to account for intracellular metabolism and to explore the role of genetic polymorphism in the TPMT enzyme on the pharmacokinetics of 6-mercaptopurine.
methodsThe developed PBPK model was extended for 6-mercaptopurine to account for intracellular metabolism and genetic polymorphism in TPMT activity. System and drug specific parameters were obtained from the literature or estimated using plasma or intracellular red blood cell concentrations of 6-mercaptopurine and its metabolites. Age-dependent changes in parameters were implemented for scaling, and variability was also introduced for simulation. The model was validated using published data.
resultsThe model was extended successfully. Parameter estimation and model predictions were satisfactory. Prediction of intracellular red blood cell concentrations of 6-thioguanine nucleotide for different TPMT phenotypes (in a clinical study that compared conventional and individualized dosing) showed results that were consistent with observed values and reported incidence of haematopoietic toxicity. Following conventional dosing, the predicted mean concentrations for homozygous and heterozygous variants, respectively, were about 10 times and two times the levels for wild-type. However, following individualized dosing, the mean concentration was around the same level for the three phenotypes despite different doses.
conclusionsThe developed PBPK model has been extended for 6-mercaptopurine and can be used to predict plasma 6-mercaptopurine and tissue concentration of 6-mercaptopurine, 6-thioguanine nucleotide and 6-methylmercaptopurine ribonucleotide in adults and children. Predictions of reported data from clinical studies showed satisfactory results. The model may help to improve 6-mercaptopurine dosing, achieve better clinical outcome and reduce toxicity.
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