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Pharmacogenetics of tacrolimus: ready for clinical translation?

ABSTRACT: Tacrolimus (Tac) exhibits an interindividual pharmacokinetic variability that affects the dose required to reach the target concentration in blood. Tac is metabolized by two enzymes of the cytochrome P450 family, CYP3A5 and CYP3A4. The effect of the CYP3A5 genotype on Tac bioavailability has been demonstrated, and the main determinant of this pharmacogenetic effect is a single-nucleotide polymorphism (SNP) in intron 3 of CYP3A5 (6986 A>G; SNP rs776746; also known as CYP3A5*3). The mean dose-adjusted blood Tac concentration was significantly higher among CYP3A5*3 homozygotes than that of carriers of the wild-type allele (CYP3A5*1). In a recent prospective study, a group of kidney transplant patients received a Tac dose either according to the CYP3A5 genotype (the adapted group) or according to the standard regimen (the control group). All patients received induction therapy with mycophenolate mofetil, corticosteroids, and either basiliximab or intravenous anti-thymocyte globulin. Patients in the adapted-dose group required 3-8 days (median 6 days) to reach the target range compared with 3-25 days (median 7 days) in the control group (P=0.001). The total number of dose modifications was also lower in the adapted-dose group. This study also suggested that the CYP3A5 genotype might contribute minimally to the reduction of early acute rejection. However, additional studies are necessary to determine whether the pharmacogenetic approach could help reduce the necessity for induction therapy and co-immunosuppressors.

SUBMITTER: Coto E

PROVIDER: S-EPMC4089617 | biostudies-literature | 2011 Aug

REPOSITORIES: biostudies-literature

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Pharmacogenetics of tacrolimus: ready for clinical translation?

Coto Eliecer E Tavira Beatriz B Suárez-Álvarez Beatriz B López-Larrea Carlos C Díaz-Corte Carmen C Ortega Francisco F Alvarez Victoria V

Kidney international supplements 20110801 2

Tacrolimus (Tac) exhibits an interindividual pharmacokinetic variability that affects the dose required to reach the target concentration in blood. Tac is metabolized by two enzymes of the cytochrome P450 family, CYP3A5 and CYP3A4. The effect of the CYP3A5 genotype on Tac bioavailability has been demonstrated, and the main determinant of this pharmacogenetic effect is a single-nucleotide polymorphism (SNP) in intron 3 of CYP3A5 (6986 A>G; SNP rs776746; also known as CYP3A5*3 ...[more]

PMID: 25028625

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Project description:Tacrolimus, an immunosuppressant used in solid organ transplantation, has a narrow therapeutic index and exhibits inter-individual pharmacokinetic variability. Achieving and maintaining a therapeutic level of the drug by giving appropriate doses is crucial for successful immunosuppression, especially during the initial post-transplant period. We studied the effect of CYP3A5, CYP3A4, and ABCB1 gene polymorphisms on tacrolimus trough concentrations in South Indian renal transplant recipients from Kerala to formulate a genotype-based dosing equation to calculate the required starting daily dose of tacrolimus to be given to each patient to attain optimal initial post-transplant period drug level. We also investigated the effect of these genes on drug-induced adverse effects and rejection episodes and looked into the global distribution of allele frequencies of these polymorphisms. One hundred forty-five renal transplant recipients on a triple immunosuppressive regimen of tacrolimus, mycophenolate mofetil, and steroid were included in this study. Clinical data including tacrolimus daily doses, trough levels (C0) and dose-adjusted tacrolimus trough concentration (C0/D) in blood at three time points (day 6, 6 months, and 1-year post-transplantation), adverse drug effects, rejection episodes, serum creatinine levels, etc., were recorded. The patients were genotyped for CYP3A5*3, CYP3A4*1B, CYP3A4*1G, ABCB1 G2677T, and ABCB1 C3435T polymorphisms by the PCR-RFLP method. We found that CYP3A5*3 polymorphism was the single most strongly associated factor determining the tacrolimus C0/D in blood at all three time points (p < 0.001). Using multiple linear regression, we formulated a simple and easy to compute equation that will help the clinician calculate the starting tacrolimus dose per kg body weight to be administered to a patient to attain optimal initial post-transplant period tacrolimus level. CYP3A5 expressors had an increased chance of rejection than non-expressors (p = 0.028), while non-expressors had an increased risk for new-onset diabetes mellitus after transplantation (NODAT) than expressors (p = 0.018). Genotype-guided initial tacrolimus dosing would help transplant recipients achieve optimal initial post-transplant period tacrolimus levels and thus prevent the adverse effects due to overdose and rejection due to inadequate dose. We observed inter-population differences in allele frequencies of drug metabolizer and transporter genes, emphasizing the importance of formulating population-specific dose prediction models to draw results of clinical relevance.

Project description:IntroductionTacrolimus is a calcineurin inhibitor used as an immunosuppressant drug in solid organ transplantation, and is mainly metabolized by cytochrome P450 (CYP) 3A4 and CYP3A5. Studies have shown an association between the CYP3A5 genotype and tacrolimus dose-adjusted trough concentrations. Variants in the genes PPARA, POR and CYP3A4 have recently been shown to influence tacrolimus metabolism. Furthermore, pharmacokinetic interaction between corticosteroid treatment and tacrolimus has been shown. In the present study, we investigated a potential association between CYP3A5*3, PPARA c.209-1003G>A, POR*28 and CYP3A4*22 and dose-adjusted tacrolimus trough concentrations in a primarily corticosteroid-free (>85%) population of Danish pediatric and adult kidney transplant recipients.MethodsSeventy-two patients receiving treatment with oral tacrolimus were genotyped using real-time polymerase chain reaction and Primer-Probe Detection. Tacrolimus trough concentrations, corresponding doses and covariates were retrospectively collected from the patients' medical charts.ResultsIt was confirmed that CYP3A5*1 wild-type carriers had lower median dose-adjusted tacrolimus trough concentrations compared with noncarriers. Adults had 56 and 77% lower trough concentrations at 6 weeks (p = 0.0003) and 1 year, respectively (p < 0.0017), and, similarly, children had 65 and 39% lower median concentrations, with p values of 0.006 and 0.011, respectively. No association was found for PPARA c.209-1003G>A, POR*28, or CYP3A4*22. An association between the PPARA c.209-1003G>A genotype and an increased number of infections with cytomegalovirus (CMV) within the first year was identified (p < 0.05). Only 29% of trough concentrations measured between 2 and 12 weeks post-transplantation were on target.ConclusionThis study shows that the known association of the CYP3A5 genotype with tacrolimus dose-adjusted trough concentrations has the same impact in a corticosteroid-sparse population. The association between PPARA variance and infections with CMV will need further investigation.

Project description:Statins are the most commonly prescribed drugs in the United States and are extremely effective in reducing major cardiovascular events in the millions of Americans with hyperlipidemia. However, many patients (up to 25%) cannot tolerate or discontinue statin therapy due to statin-induced myopathy (SIM). Patients will continue to experience SIM at unacceptably high rates or experience unnecessary cardiovascular events (as a result of discontinuing or decreasing their statin therapy) until strategies for predicting or mitigating SIM are identified. A promising strategy for predicting or mitigating SIM is pharmacogenetic testing, particularly of pharmacokinetic genetic variants as SIM is related to statin exposure. Data is emerging on the association between pharmacokinetic genetic variants and SIM. A current, critical evaluation of the literature on pharmacokinetic genetic variants and SIM for potential translation to clinical practice is lacking. This review focuses specifically on pharmacokinetic genetic variants and their association with SIM clinical outcomes. We also discuss future directions, specific to the research on pharmacokinetic genetic variants, which could speed the translation into clinical practice. For simvastatin, we did not find sufficient evidence to support the clinical translation of pharmacokinetic genetic variants other than SLCO1B1. However, SLCO1B1 may also be clinically relevant for pravastatin- and pitavastatin-induced myopathy, but additional studies assessing SIM clinical outcome are needed. CYP2D6*4 may be clinically relevant for atorvastatin-induced myopathy, but mechanistic studies are needed. Future research efforts need to incorporate statin-specific analyses, multi-variant analyses, and a standard definition of SIM. As the use of statins is extremely common and SIM continues to occur in a significant number of patients, future research investments in pharmacokinetic genetic variants have the potential to make a profound impact on public health.

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Pharmacogenetics of tacrolimus: ready for clinical translation?

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Pharmacogenetics of tacrolimus: ready for clinical translation?

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