Impact of CYP3A4*22 Allele on Sirolimus Dose Requirement in Kidney Transplant Patients

Abstract

Background: Sirolimus (SRL) is a substrate of Cytochrome P450 3A4 (CYP3A4). Interindividual variability in SRL pharmacokinetics complicates effective therapy, making therapeutic drug monitoring a necessity. Recently, a newly discovered intronic single nucleotide polymorphism (SNP) in CYP3A4 (CYP3A4*22, rs35599367C>T, MAF 3-5%), has been linked to reduced hepatic expression and activity of CYP3A4. Methods: 81 kidney transplant recipients receiving SRL once daily as part as their immunosuppressive therapy were considered to enter the study. Among them, 38 patients were given SRL from the early period after kidney transplantation (de novo group) and 43 were switched to SRL mainly for chronic allograft nephropathy or neoplasia (switched group). SRL trough levels (C0) were measured at steady state and all patients were genotyped for the new CYP3A4*22 allele. SRL C0 (ng/ml), daily dose (mg/kg body weight), and SRL dose-adjusted C0 were compared across genotype groups. For the interpretation of the data, patients were also genotyped for the CYP3A5*3 loss-of-function allele. Results: Five patients carried the CYP3A4*22 variant allele, 7 patients were categorized as CYP3A5 expressers (i.e. at least one CYP3A5*1 active allele), yielding allelic frequencies of 3.1 and 4.3%, respectively. In the whole population, a trend for higher SRL dose-adjusted C0 was observed for CYP3A4*22 carriers (338.3 versus 209.6 ng/ml per mg/kg, figure 1A, p=0.09). Combining CYP3A4*22 and CYP3A5*3 genotypes showed a linear trend in SRL dose-adjusted C0 according to the allelic status of the patient with poor (CYP3A4*22 carriers; CYP3A5*3/*3) and intermediate (CYP3A4*1/*1; CYP3A5*3/*3) CYP3A metabolizers showing +94.7% and +22.8% higher SRL dose-adjusted C0 when compared to extensive (CYP3A4*1/*1; CYP3A5*1 carriers) CYP3A metobolizers, respectively (p linear trend=0.09, figure 1B). In a multiple linear regression analysis, we observed that SRL dose-adjusted C0 correlated with time after transplantation [months] (b=0.09, p=0.001) and the CYP3A4*22 allele (b=131.1, p=0.06). Together, both parameters explained 16% of the variability observed in SRL dose-adjusted C0 with 4% attributable to the CYP3A4*22 allelic status of the patient. Conclusions: In this study, we found indications that the CYP3A4*22 allele decreases the ability to metabolize SRL, comparable as to the effect of this SNP on calineurin inhibitor pharmacokinetics. This pilot study should be further investigated in more powered longitudinal studies assessing both the pharmacokinetic and pharmacodynamic impact (e.g. occurence of SRL-related adverse events and/or efficacy) of CYP3A4*22.[Figure 1A and 1B]