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

Overview

Journal Eur J Drug Metab Pharmacokinet

Date 2018 Nov 25

PMID 30471066

Authors

Wai-Ping Yau

Charlene Wei-Ting Loh

Anantharaman Vathsala

Affiliations

Soon will be listed here.

Abstract

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 (AUC) 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, AUC 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.

References

Jones D, Gorski J, Hamman M, Mayhew B, Rider S, Hall S . Diltiazem inhibition of cytochrome P-450 3A activity is due to metabolite intermediate complex formation. J Pharmacol Exp Ther. 1999; 290(3):1116-25. View

Hoffmeyer S, Burk O, von Richter O, Arnold H, Brockmoller J, Johne A . Functional polymorphisms of the human multidrug-resistance gene: multiple sequence variations and correlation of one allele with P-glycoprotein expression and activity in vivo. Proc Natl Acad Sci U S A. 2000; 97(7):3473-8. PMC: 16264. DOI: 10.1073/pnas.97.7.3473. View

Lamba J, Lin Y, Thummel K, Daly A, Watkins P, Strom S . Common allelic variants of cytochrome P4503A4 and their prevalence in different populations. Pharmacogenetics. 2002; 12(2):121-32. DOI: 10.1097/00008571-200203000-00006. View

Anglicheau D, Verstuyft C, Laurent-Puig P, Becquemont L, Schlageter M, Cassinat B . Association of the multidrug resistance-1 gene single-nucleotide polymorphisms with the tacrolimus dose requirements in renal transplant recipients. J Am Soc Nephrol. 2003; 14(7):1889-96. DOI: 10.1097/01.asn.0000073901.94759.36. View

Hardinger K, Park J, Schnitzler M, Koch M, Miller B, Brennan D . Pharmacokinetics of tacrolimus in kidney transplant recipients: twice daily versus once daily dosing. Am J Transplant. 2004; 4(4):621-5. DOI: 10.1111/j.1600-6143.2004.00383.x. View

Kothari J, Nash M, Zaltzman J, Prasad G . Diltiazem use in tacrolimus-treated renal transplant recipients. J Clin Pharm Ther. 2004; 29(5):425-30. DOI: 10.1111/j.1365-2710.2004.00578.x. View

Tsuchiya N, Satoh S, Tada H, Li Z, Ohyama C, Sato K . Influence of CYP3A5 and MDR1 (ABCB1) polymorphisms on the pharmacokinetics of tacrolimus in renal transplant recipients. Transplantation. 2004; 78(8):1182-7. DOI: 10.1097/01.tp.0000137789.58694.b4. View

Alloway R, Steinberg S, Khalil K, Gourishankar S, Miller J, Norman D . Conversion of stable kidney transplant recipients from a twice daily Prograf-based regimen to a once daily modified release tacrolimus-based regimen. Transplant Proc. 2005; 37(2):867-70. DOI: 10.1016/j.transproceed.2004.12.222. View

Alloway R, Steinberg S, Khalil K, Gourishankar S, Miller J, Norman D . Two years postconversion from a prograf-based regimen to a once-daily tacrolimus extended-release formulation in stable kidney transplant recipients. Transplantation. 2007; 83(12):1648-51. DOI: 10.1097/01.tp.0000264056.20105.b4. View

10.

Loh P, Lou H, Zhao Y, Chin Y, Vathsala A . Significant impact of gene polymorphisms on tacrolimus but not cyclosporine dosing in Asian renal transplant recipients. Transplant Proc. 2008; 40(5):1690-5. DOI: 10.1016/j.transproceed.2008.04.010. View

11.

Wallemacq P, Goffinet J, OMorchoe S, Rosiere T, Maine G, Labalette M . Multi-site analytical evaluation of the Abbott ARCHITECT tacrolimus assay. Ther Drug Monit. 2009; 31(2):198-204. DOI: 10.1097/FTD.0b013e31819c6a37. View

12.

Levey A, Stevens L, Schmid C, Zhang Y, Castro 3rd A, Feldman H . A new equation to estimate glomerular filtration rate. Ann Intern Med. 2009; 150(9):604-12. PMC: 2763564. DOI: 10.7326/0003-4819-150-9-200905050-00006. View

13.

Diez Ojea B, Alonso Alvarez M, Aguado Fernandez S, Banos Gallardo M, Garcia Melendreras S, Gomez Huertas E . Three-month experience with tacrolimus once-daily regimen in stable renal allografts. Transplant Proc. 2009; 41(6):2323-5. DOI: 10.1016/j.transproceed.2009.06.048. View

14.

Staatz C, Goodman L, Tett S . Effect of CYP3A and ABCB1 single nucleotide polymorphisms on the pharmacokinetics and pharmacodynamics of calcineurin inhibitors: Part I. Clin Pharmacokinet. 2010; 49(3):141-75. DOI: 10.2165/11317350-000000000-00000. View

15.

Press R, de Fijter J, Guchelaar H . Individualizing calcineurin inhibitor therapy in renal transplantation--current limitations and perspectives. Curr Pharm Des. 2010; 16(2):176-86. DOI: 10.2174/138161210790112782. View

16.

Thervet E, Loriot M, Barbier S, Buchler M, Ficheux M, Choukroun G . Optimization of initial tacrolimus dose using pharmacogenetic testing. Clin Pharmacol Ther. 2010; 87(6):721-6. DOI: 10.1038/clpt.2010.17. View

17.

Li J, Wang X, Chen S, Liu L, Fu Q, Chen X . Effects of diltiazem on pharmacokinetics of tacrolimus in relation to CYP3A5 genotype status in renal recipients: from retrospective to prospective. Pharmacogenomics J. 2010; 11(4):300-6. DOI: 10.1038/tpj.2010.42. View

18.

Glowacki F, Lionet A, Hammelin J, Labalette M, Provot F, Hazzan M . Influence of cytochrome P450 3A5 (CYP3A5) genetic polymorphism on the pharmacokinetics of the prolonged-release, once-daily formulation of tacrolimus in stable renal transplant recipients. Clin Pharmacokinet. 2011; 50(7):451-9. DOI: 10.2165/11587050-000000000-00000. View

19.

Iaria G, Sforza D, Angelico R, Toti L, De Luca L, Manuelli M . Switch from twice-daily tacrolimus (Prograf) to once-daily prolonged-release tacrolimus (Advagraf) in kidney transplantation. Transplant Proc. 2011; 43(4):1028-9. DOI: 10.1016/j.transproceed.2011.01.130. View

20.

Barraclough K, Isbel N, Johnson D, Campbell S, Staatz C . Once- versus twice-daily tacrolimus: are the formulations truly equivalent?. Drugs. 2011; 71(12):1561-77. DOI: 10.2165/11593890-000000000-00000. View