Cyclosporine and tacrolimus are immunosuppressive drugs largely used in renal transplantation. They are characterized by a wide inter-individual variability in their pharmacokinetics with a potential impact on their therapeutic efficacy or induced toxicity. CYP3A5 and P-glycoprotein appear as important determinants of the metabolism of these drugs. The objective of this study was to investigate the effect of CYP3A5 and MDR1 (ABCB1) polymorphisms on cyclosporine and tacrolimus dose requirements and trough blood concentrations in stable transplant patients. Stable renal transplant recipients receiving cyclosporine (n = 50) or tacrolimus (n = 50) were genotyped for CYP3A5*3 and *6, and MDR1 C1236T, G2677T/A and C3435T. Dose-adjusted trough blood levels (ng/ml per mg/kg body weight) as well as doses (mg/kg body weight) required to achieve target blood concentrations were compared among patients according to allelic status for CYP3A5 and MDR1. Dose-adjusted trough concentrations were three-fold and 1.6-fold higher in CYP3A5*3/*3 patients than in CYP3A5*1/*3 patients for tacrolimus and cyclosporine, respectively. In the case of tacrolimus, the difference was even more striking when considering CYP3A5*1/*1 patients showing dose-adjusted trough concentrations 5.8-fold lower than CYP3A5*3/*3 patients. For both drugs, no association was found between trough blood concentrations or dose requirement and MDR1 genotype. Multiple regression analyses showed that CYP3A5*1/*3 polymorphism explained up to 45% of the variability in dose requirement in relation to tacrolimus use. Given the importance of rapidly achieving target blood concentrations after transplantation, further prospective studies should consider the immediate post-graft period and assess the influence of this specific polymorphism. Beside non-genetic factors (e.g. steroids dosing, drugs interactions), CYP3A5 pharmacogenetic testing performed just before transplantation could contribute to a better individualization of immunosuppressive therapy.

Genetic polymorphisms in biotransformation enzyme CYP3A5 (6986G >A

No abstract

Unlike tacrolimus, sirolimus adjusted trough concentrations and dose requirements seem not affected by CYP3A5 and MDR1 polymorphisms. Adjusted-prednisone dose has a significant impact on tacrolimus and sirolimus dose requirements.

Background: Mycophenolate mofetil (MMF) is widely used in organ transplantation to prevent acute rejection. Because MMF can produce hematologic and/or gastrointestinal toxicity, therapeutic monitoring is becoming mandatory. This study was designed to investigate the relationship between the clinical events and the pharmacokinetics of mycophenolic acid (MPA) in adult renal transplantation. Methods: Thirty-one adult kidney recipients were prospectively included in the study. MPA pharmacokinetic profiles (blood sampling at 0, 0.5, 1, 2, 4, 6, and 12 h after MMF oral dose) were obtained after transplantation (desired creatinine clearance, 40 mL/min), at 3 months after grafting, and at every clinical event (e.g., side effect or rejection). All patients received a 10-day course of anti-thymocyte globulin, cyclosporine, MMF (1 g twice daily), and steroids. Results: We divided the 31 patients into two groups (groups 1 and 2). Ten patients (32%; group 1) had uneventful outcomes, and 21 patients (68%; group 2) presented with MPA-related side effects. For groups 1 and 2, the MPA trough concentrations (Cmin) were 1.63 ± 1.07 and 2.29 ± 1.16 mg/L, respectively (P = 0.06), and the areas under the curve (AUCs) for MPA from t0 to t12 h (MPA-AUC0–12h) were 39.80 ± 15.29 and 62.10 ± 21.07 mg · h/L, respectively (P = 0.0005, two-sample t-test). Three patients experienced acute graft rejection after the oral MMF dose was reduced because of side effects. In this group, the MPA-Cmin and MPA-AUC were significantly lower by the time acute rejection occurred (1.00 ± 0.45 mg/L and 25.00 ± 6.20 mg · h/L, respectively). At a fixed dose (1 g twice per day), we compared the pharmacokinetic parameters of MPA [Cmin, the MPA concentration 30 min after the oral dose of MMF (C30), and AUC] according to the presence or absence of side effects in the two groups. Cmin and AUC did not differ between the two groups [Cmin = 2.22 ± 1.13 vs 2.17 ± 1.13 mg/L (P = 0.9); AUC = 66.82 ± 29.87 vs 55.70 ± 11.74 mg · h/L (P = 0.11)]; and C30 was significantly higher in group 2 than in group 1 (C30 = 32.99 ± 12.59 vs 7.45 ± 5.40 mg/L; P <0.0001). Conclusions: Our results demonstrate a pharmacokinetic/pharmacodynamic relationship between MPA and clinical events. At a fixed dose of 2 g/day, a high C30 is associated with increased risk for side effects. This study suggests that dividing the MMF daily oral dose into more than two divided doses might prevent early MPA toxicity.