Conversion from Twice-Daily Prograf® to Once-Daily Advagraf® in Multi-ethnic Asian Adult Renal Transplant Recipients With or Without Concomitant Use of Diltiazem: Impact of CYP3A5 and MDR1 Genetic Polymorphisms on Tacrolimus Exposure
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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.
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.
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.
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.
The authors thank Ms. Tanusya Murali and the clinical care team for their assistance with patient recruitment, study coordination, and data collection. This study was presented in part at the 26th International Congress of The Transplantation Society (TTS 2016) in Hong Kong on 21 August 2016.
Compliance with Ethical Standards
This work was supported by an Astellas Pharma Inc. Investigator Initiated Study Grant. Financial support included funding for: (1) genotyping of CYP3A5 rs776746 (CYP3A5*3) and MDR1 rs1045642 (MDR1 C3435T), (2) the trial coordinator, (3) pharmacokinetic studies, (4) standardized meals during pharmacokinetic studies, (5) Prograf® and Advagraf®, and (6) laboratory tests performed as part of the study protocol.
Conflict of interest
A. Vathsala has received honoraria from Astellas Pharma Inc. for talks given at scientific meetings. W.P. Yau and C.W.T. Loh declare that they have no conflict of interest.
This study was approved by the National Healthcare Group Domain Specific Review Board (NHG DSRB ref: 2012/01026) and granted a Clinical Trial Certificate (certificate number: CTC1300029) by the Health Sciences Authority, Singapore. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.
Informed consent was obtained from all individual participants included in the study.
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