A Markov Chain Model to Evaluate the Effect of CYP3A5 and ABCB1 Polymorphisms on Adverse Events Associated with Tacrolimus in Pediatric Renal Transplantation

• Published in: The AAPS journal Vol. 15; no. 4; pp. 1189 - 1199
• Main Authors: Sy, Sherwin K. B., Heuberger, Jules, Shilbayeh, Sireen, Conrado, Daniela J., Derendorf, Hartmut
• Format: Journal Article
• Language: English
• Published: Boston Springer US 01.10.2013
• Subjects: Adolescent; Adult; ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily B, Member 1 - genetics; Biochemistry; Biomedical and Life Sciences; Biomedicine; Biotechnology; Child; Child, Preschool; Cytochrome P-450 CYP3A - genetics; Female; Gene Frequency - genetics; Humans; Immunosuppressive Agents - adverse effects; Immunosuppressive Agents - blood; Kidney Transplantation - adverse effects; Male; Markov Chains; Middle Aged; Pharmacology/Toxicology; Pharmacy; Polymorphism, Single Nucleotide - genetics; Research Article; Retrospective Studies; Tacrolimus - adverse effects; Tacrolimus - blood; Young Adult; ABCB1; adverse events; Markov; CYP3A5; tacrolimus
• ISSN: 1550-7416; 1550-7416
• DOI: 10.1208/s12248-013-9528-9

The SNP A6986G of the CYP3A5 gene (*3) results in a non-functional protein due to a splicing defect whereas the C3435T was associated with variable expression of the ABCB1 gene, due to protein instability. Part of the large interindividual variability in tacrolimus efficacy and toxicity can be accounted for by these genetic factors. Seventy-two individuals were examined for A6986G and C3435T polymorphism using a PCR-RFLP-based technique to estimate genotype and allele frequencies in the Jordanian population. The association of age, hematocrit, platelet count, CYP3A5 , and ABCB1 polymorphisms with tacrolimus dose- and body-weight-normalized levels in the subset of 38 pediatric renal transplant patients was evaluated. A Markov model was used to evaluate the time-dependent probability of an adverse event occurrence by CYP3A5 phenotypes and ABCB1 genotypes. The time-dependent probability of adverse event was about double in CYP3A5 non-expressors compared to the expressors for the first 12 months of therapy. The CYP3A5 non-expressors had higher corresponding normalized tacrolimus levels compared to the expressors in the first 3 months. The correlation trend between probability of adverse events and normalized tacrolimus concentrations for the two CYP3A5 phenotypes persisted for the first 9 months of therapy. The differences among ABCB1 genotypes in terms of adverse events and normalized tacrolimus levels were only observed in the first 3 months of therapy. The information on CYP3A5 genotypes and tacrolimus dose requirement is important in designing effective programs toward management of tacrolimus side effects particularly for the initial dose when tacrolimus blood levels are not available for therapeutic drug monitoring.