Kayode Ogungbenro and Leon Aarons
Manchester Pharmacy School, The University of Manchester, Manchester, M13 9PT, United Kingdom
Objectives: To develop a PBPK model for 6-MP in childhood acute lymphoblastic leukaemia (ALL). 6-mercaptopurine is a purine antimetabolite and prodrug that undergoes extensive intracellular metabolism to produce thionucleotides, active metabolites which have cytotoxic and immunosuppressive properties [1]. Combination therapies involving 6-mercaptopurine and methotrexate have shown remarkable results in the cure of childhood ALL in the last 30 years [2]. 6-mercaptopurine undergoes very extensive intestinal and hepatic metabolism following dosing due to the activity of xanthine oxidase leading to very low and highly variable bioavailability [3]. Despite the success recorded in its use there is still lack of effect and presence of life threatening toxicity in some patients due to variability in the pharmacokinetics. Also, dose adjustment during treatment is still based on toxicity [4].
Methods: A physiologically based pharmacokinetic model with separate compartments for plasma, red blood cells, liver, gut tissue, enterocyte, stomach, gut lumen, kidney, skin, bone marrow, spleen, thymus muscle and rest of body was developed. System parameters such as blood flows and organ volumes were obtained from the literature, some drug parameters were obtained from the literature and the rest were optimised from studies reporting plasma and intracellular red blood cell concentrations of 6-merpatopurine and its metabolites. Age-dependent changes in parameters were implemented for scaling and variability was also introduced on the parameters for prediction. The effect of genetic polymorphism in thiopurine methyltransferase was also investigated.
Results: The model adequately predicts plasma concentration after intravenous and oral doses in adults and children. The model also provides encouraging results in terms of the prediction of the concentration of 6-mercaptopurine and its metabolites in plasma and red blood cells (RBC) in the different polymorphic groups. For a standard oral dose of 75mg/m2, the concentration of 6-thioguanine nucleotide in RBC is about 30 and 2 times higher for the no activity and intermediate activity groups compared to the high activity groups respectively.
Conclusions: A physiologically based pharmacokinetic model that can predict concentrations in different tissues has been developed and this can be used for dose optimisation. This model could help to improve clinical outcome in the use of 6-mercaptopurine through better dosing.
References:
[1] Innocenti F, Danesi R, Di Paolo A, Loru B, Favre C, Nardi M, Bocci G, Nardini D, Macchia P, Del Tacca M (1996) Clinical and experimental pharmacokinetic interaction between 6-mercaptopurine and methotrexate. Cancer Chemother Pharmacol 37: 409-414.
[2] Cheok MH, Evans WE (2006) Acute lymphoblastic leukaemia: a model for the pharmacogenomics of cancer therapy. Nat Rev Cancer 6: 117-129.
[3] Zimm S, Collins JM, Riccardi R, O’Neill D, Narang PK, Chabner B, Poplack DG (1983) Variable bioavailability of oral mercaptopurine. Is maintenance chemotherapy in acute lymphoblastic leukemia being optimally delivered? N Engl J Med 308: 1005-1009.
[4] Balis FM, Holcenberg JS, Poplack DG, Ge J, Sather HN, Murphy RF, Ames MM, Waskerwitz MJ, Tubergen DG, Zimm S, Gilchrist GS, Bleyer WA (1998) Pharmacokinetics and pharmacodynamics of oral methotrexate and mercaptopurine in children with lower risk acute lymphoblastic leukemia: a joint children’s cancer group and pediatric oncology branch study. Blood 92: 3569-3577.
Reference: PAGE 23 () Abstr 3072 [www.page-meeting.org/?abstract=3072]
Poster: Drug/Disease modeling - Absorption & PBPK