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

Journal Title: The AAPS Journal - Year 2013, Vol 15, Issue 4

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 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.

Authors and Affiliations

Sherwin K. B. Sy, Jules Heuberger, Sireen Shilbayeh, Daniela J. Conrado, Hartmut Derendorf

Keywords

Related Articles

How Minimally Invasive is Microdialysis Sampling? A Cautionary Note for Cytokine Collection in Human Skin and other Clinical Studies

It is common to refer to microdialysis as a minimally invasive procedure, likening it to insertion of an artificial capillary. While a comparison of this type allows the process to be easily visualized by those outside t...

Comparison of Drug Permeabilities and BCS Classification: Three Lipid-Component PAMPA System Method versus Caco-2 Monolayers

PC18:1 and PS18:1 were purchased from Avanti Polar Lipids (Alabaster, AL). Hydrophobic microfilter plates (polyvinylidene fluoride, 0.45 μm) were purchased from Millipore Corporation (Bedford, MA). Caco-2...

Using DTA and DTAARRAY Variables and Programming in WinNonlin ASCII Models to Streamline User-Defined Calculation and Data Analysis

The online version of this article (doi:10.1208/s12248-014-9711-7) contains supplementary material, which is available to authorized users.

A Neutralizing Antibody Assay Based on a Reporter of Antibody-Dependent Cell-Mediated Cytotoxicity

Benralizumab is a humanized anti-IL5 receptor α (IL5Rα) monoclonal antibody (mAb) with enhanced (afucosylation) antibody-dependent cell-mediated cytotoxicity (ADCC) function. An ADCC reporter cell-based n...

Clinical Immunogenicity of rHuPH20, a Hyaluronidase Enabling Subcutaneous Drug Administration

The online version of this article (doi:10.1208/s12248-015-9782-0) contains supplementary material, which is available to authorized users.

Download PDF file
  • EP ID EP681176
  • DOI  10.1208/s12248-013-9528-9
  • Views 78
  • Downloads 0

How To Cite

Sherwin K. B. Sy, Jules Heuberger, Sireen Shilbayeh, Daniela J. Conrado, Hartmut Derendorf (2013). A Markov Chain Model to Evaluate the Effect of CYP3A5 and ABCB1 Polymorphisms on Adverse Events Associated with Tacrolimus in Pediatric Renal Transplantation. The AAPS Journal, 15(4), -. https://europub.co.uk/articles/-A-681176