Background and objectives: Tacrolimus is the mainstay of immunosuppression in renal transplantation. Given that once-daily administration improves patient compliance, 1:1 dose conversion from twice-daily Prograf® to once-daily Advagraf® is recommended. Although cytochrome P450 (CYP) 3A5 and multi-drug resistance 1 (MDR1) polymorphisms influence tacrolimus concentrations, it is unknown if these impact on conversion. This study investigated the change in the pharmacokinetics of tacrolimus after conversion from Prograf® to Advagraf® and examined the impact of CYP3A5 and MDR1 C3435T polymorphisms on those pharmacokinetics.
Methods: A prospective open-label pharmacokinetic study of 1:1 conversion from Prograf® to Advagraf® with or without diltiazem was conducted on 26 stable renal transplant recipients. Blood samples were collected over 24 h during each phase, tacrolimus concentrations were assayed, and noncompartmental pharmacokinetic analysis was performed. All participants were genotyped for CYP3A5*3 and MDR1 C3435T.
Results: After conversion, without diltiazem, the area under the concentration-time curve at steady state from 0 to 24 h after dose administration (AUCss, 0-24) was significantly reduced [median 224 (range 172-366) vs. 184 (104-347) ng·h/mL, p = 0.006, n = 26]. A decrease in tacrolimus exposure (median 21%) was only evident among CYP3A5 expressors [227 (172-366) vs. 180 (104-347) ng·h/mL, p = 0.014, n = 18], not among non-expressors [215 (197-290) vs. 217 (129-281) ng·h/mL, p = 0.263, n = 8]. In contrast, among CYP3A5 expressors receiving diltiazem, AUCss, 0-24 did not change significantly upon conversion [229 (170-296) vs. 221 (123-342) ng·h/mL, p = 0.575, n = 10]. An independent effect was not evident for MDR1 C3435T polymorphism.
Conclusion: The high prevalence of CYP3A5 polymorphism among Asians may lead to a significant reduction in tacrolimus exposure with 1:1 dose conversion of Prograf® to Advagraf®. These results advocate for CYP3A5 determination prior to conversion, and suggest that 1:1.25 conversion should be used for CYP3A5 expressors and 1:1 conversion for other patients.