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

Abstract

Abstract. 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 timedependent 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.

Pharmacokinetics and Toxicity of Tacrolimus Early After Heart and Lung Transplantation

“…Due to these large differences in CYP3A expression between individuals, it may be beneficial to identify CYP3A expression before transplantation to better predict tacrolimus blood concentrations and reduce (nephro-) toxicity directly after transplantation (50).…”

Anaemia associated with Tacrolimus: A case report and literature review

“…Researchers found that when the SNP A6986G (*3) of CYP3A5 produces a non‐functional protein due to splicing defects, and patients with defects in the CYP3A5 expression are more susceptible to ADRs in their first year of taking FK506. These reactions include anaemia, thrombocytopenia and hypokalaemia, at a rate doubling than that of patients without this defect 11 . At present, the frequency of mutant alleles in Asian people (Chinese and Japanese) is between 66.7% and 75%. Both FK506 and sirolimus are macrolide immunosuppressants.…”

The impact of tacrolimus exposure on extrarenal adverse effects in adult renal transplant recipients

“…Therefore, the entire population model may provide a better tool for identifying individual CL/F values than using genotypes alone. Another investigation explored the impact of CYP3A5*3 genotypes only on tacrolimus renal and extrarenal AEs across time using a Markov chain model and concluded that the probability of an adverse event occurrence in the first 3 months in the CYP3A5 nonexpressers is 2‐fold greater compared to the CYP3A5 expressers . Another important genomic contribution to AE manifestations are the ABCB1 SNPs, 1236C > T (rs1128503 ), 2677G > T/A (rs2032582), and 3435C > T (rs1045642) variants that encode for P‐glycoprotein and modulates cellular distribution of tacrolimus.…”