Share this article on:

Lower Variability in 24-Hour Exposure During Once-Daily Compared to Twice-Daily Tacrolimus Formulation in Kidney Transplantation

Stifft, Frank1; Stolk, Leo M.L.2; Undre, Nasrullah3; van Hooff, Johannes P.1; Christiaans, Maarten H.L.1,4

doi: 10.1097/01.TP.0000437561.31212.0e
Clinical and Translational Research

Introduction: Tacrolimus has originally been registered as a twice-daily formulation (Prograf, Tac BID), although a once-daily formulation (Advagraf, Tac QD) is also available. A reduced intrapatient variability of Tac Cmin, a surrogate marker for 24-hour drug exposure (AUC0–24), has been suggested. The variability of AUC0–24 has never been studied prospectively yet. The purpose of this study was to investigate the change in intrapatient variability of Tac AUC0–24 after converting from Tac BID to Tac QD.

Methods: Forty renal transplant patients on Tac BID were converted on a 1:1 (mg/mg) basis to Tac QD in an investigator-driven comparative pharmacokinetic (PK) study. AUC0–24 was determined five times before and after conversion. Duplicate samples were collected by the patients themselves using the dried blood spot method. The main outcome measure is the change in intrapatient variability of AUC0–24 expressed as coefficient of variation (CV). Moreover, the influence of Cyp3A5 genotype polymorphism on the change in CV was studied.

Results: In total, 400 AUC0–24 profiles were available for analysis. Conversion to Tac QD resulted in a significant improvement in intra-patient CV from 14.1% to 10.9% (P=0.012). Patients with the Cyp3A5*1/*3 genotype (n=11) had a numerically larger improvement in CV than patients with the CYP3A5*3/*3 genotype.

Conclusion: Intrapatient CV of Tac AUC0–24 improved after converting from Tac BID to Tac QD in stable renal transplant patients, especially in patients with the CYP3A5*1/3 genotype. Given the very strict protocol of this PK study, this improvement is most likely due to the different intrinsic PK properties of Tac QD and Tac BID.

1 Department of Internal Medicine, Division of Nephrology, Maastricht University Medical Centre, Maastricht, The Netherlands.

2 Department of Clinical Pharmacology and Toxicology, Maastricht University Medical Centre, Maastricht, The Netherlands.

3 Astellas Pharma Europe Ltd., Chertsey, United Kingdom.

4 Address correspondence to: Maarten H.L. Christiaans, Department of Internal Medicine, Maastricht University Medical Centre, P. Debyelaan 25, 6229 HX Maastricht, The Netherlands.

F.S. and L.S. declare no conflicts of interests. N.U. is an employee of Astellas. J.v.H. and M.H.L.C. participated in trials sponsored by Astellas and have received lecture fees from Astellas.

This investigator-driven study was performed with an unrestricted grant from Astellas Pharma Europe Ltd.

E-mail: m.christiaans@mumc.nl

F.S. participated in performing the research, analyzing data, and writing of the article. L.S. contributed analytical tools and participated in the revision of the article. N.U. contributed to the research design and participated in the revision of the article. J.v.H. participated in the research design and writing of the article. M.H.L.C. is the principal investigator and participated in the research design and writing of the article.

Received 24 June 2013. Revision requested 9 July 2013.

Accepted 10 October 2013.

Accepted December 16, 2013

© 2014 by Lippincott Williams & Wilkins