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Physiologically based pharmacokinetic modelling of methotrexate and 6-mercaptopurine in adults and children. Part 2: 6-mercaptopurine and its interaction with methotrexate
- Source :
- Journal of Pharmacokinetics and Pharmacodynamics. 41:173-185
- Publication Year :
- 2014
- Publisher :
- Springer Science and Business Media LLC, 2014.
-
Abstract
- 6-mercaptopurine (6-MP) is a purine antimetabolite and prodrug that undergoes extensive intracellular metabolism to produce thionucleotides, active metabolites which have cytotoxic and immunosuppressive properties. Combination therapies involving 6-MP and methotrexate have shown remarkable results in the cure of childhood acute lymphoblastic leukaemia (ALL) in the last 30 years. 6-MP undergoes very extensive intestinal and hepatic metabolism following oral dosing due to the activity of xanthine oxidase leading to very low and highly variable bioavailability and methotrexate has been demonstrated as an inhibitor of xanthine oxidase. Despite the success recorded in the use of 6-MP in ALL, there is still lack of effect and life threatening toxicity in some patients due to variability in the pharmacokinetics of 6-MP. Also, dose adjustment during treatment is still based on toxicity. The aim of the current work was to develop a mechanistic model that can be used to simulate trial outcomes and help to improve dose individualisation and dosage regimen optimisation. A physiological based pharmacokinetic model was proposed for 6-MP, this model has compartments for stomach, gut lumen, enterocyte, gut tissue, spleen, liver vascular, liver tissue, kidney vascular, kidney tissue, skin, bone marrow, thymus, muscle, rest of body and red blood cells. The model was based on the assumption of the same elimination pathways in adults and children. Parameters of the model include physiological parameters and drug-specific parameter which were obtained from the literature or estimated using plasma and red blood cell concentration data. Age-dependent changes in parameters were implemented for scaling and variability was also introduced on the parameters for prediction. Inhibition of 6-MP first-pass effect by methotrexate was implemented to predict observed clinical interaction between the two drugs. The model was developed successfully and plasma and red blood cell concentrations were adequately predicted both in terms of mean prediction and variability. The predicted interaction between 6-MP and methotrexate was slightly lower than the reported clinical interaction between the two drugs. The model can be used to predict plasma and tissue concentration in adults and children following oral and intravenous dosing and may ultimately help to improve treatment outcome in childhood ALL patients.
- Subjects :
- Antimetabolites, Antineoplastic
Physiologically based pharmacokinetic modelling
Adolescent
Administration, Oral
Pharmacology
Models, Biological
Young Adult
chemistry.chemical_compound
Pharmacokinetics
Antineoplastic Combined Chemotherapy Protocols
medicine
Humans
Computer Simulation
Drug Interactions
Tissue Distribution
Child
Xanthine oxidase
Mercaptopurine
business.industry
Infant, Newborn
Infant
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Methotrexate
medicine.anatomical_structure
chemistry
Child, Preschool
Toxicity
Administration, Intravenous
Bone marrow
business
Drug metabolism
medicine.drug
Subjects
Details
- ISSN :
- 15738744 and 1567567X
- Volume :
- 41
- Database :
- OpenAIRE
- Journal :
- Journal of Pharmacokinetics and Pharmacodynamics
- Accession number :
- edsair.doi.dedup.....846107dff0a013f76ad1417e8b4bb6ec