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Tacrolimus Pharmacokinetics of Once- Versus Twice-Daily Formulations in De Novo Kidney Transplantation: A Substudy of a Randomized Phase III Trial.

Wlodarczyk, Zbigniew MD, PhD*; Ostrowski, Marek MD, PhD; Mourad, Michel MD, PhD; Krämer, Bernhard K. MD, PhD§; Abramowicz, Daniel MD, PhD; Oppenheimer, Federico MD, PhD; Miller, Derek MBChB, FCP(SA)**; Dickinson, James MSc††; Undre, Nasrullah PhD‡‡

doi: 10.1097/FTD.0b013e31824d1620
Original Article

Background Tacrolimus is a well-established immunosuppressive agent for the treatment and prevention of solid organ graft rejection. It is available as an immediate-release, twice-daily formulation (Tacrolimus BID) and a prolonged-release, once-daily formulation (Tacrolimus QD). In a previous study of the pharmacokinetics (PK) of these formulations, mean systemic exposure [area under the curve from 0 to 24 hours (AUC0–24)] of tacrolimus on day 1 was approximately 30% lower for Tacrolimus QD than for Tacrolimus BID; by day 14, systemic exposure was similar; however, the mean dose of Tacrolimus QD was higher to achieve similar systemic exposure as Tacrolimus BID.

Methods To further compare the PK of the tacrolimus formulations during the first 2 weeks posttransplant, a substudy was performed in a subset of patients enrolled into a phase III trial in de novo kidney transplant recipients comparing Tacrolimus QD and Tacrolimus BID. To minimize the difference in exposure observed in the earlier study, tacrolimus therapy was initiated before transplant. The PK analysis set comprised 34 patients (17 patients per treatment group) who had 4 complete PK profiles and no major PK-related protocol violations.

Results Mean AUC0–24 of tacrolimus on day 1 was approximately 16% lower for Tacrolimus QD than for Tacrolimus BID, although by day 3 onward, the exposure was similar between treatment groups. Analysis of dose-normalized AUC0–24 (dose normalized to 0.1 mg/kg) showed a similar pattern. There was a good correlation between AUC0–24 and concentration of tacrolimus at 24 hours postdose for both formulations (Tacrolimus QD, r = 0.87; Tacrolimus BID, r = 0.92), and the slope of the line of best fit was similar.

Conclusions These results suggest that initiating tacrolimus therapy before transplant reduces the difference in exposure between Tacrolimus QD and Tacrolimus BID.

*Collegium Medicum, Szpital Uniwersytecki im. Jurasza, Bydgoszcz

General and Transplantology Surgery, Samodzielny Publiczny Szpital Kliniczny nr 2, Szczecin, Poland

Unite de Transplantation Renale et de Chirurgie, Cliniques Universitaires Saint-Luc, Brussels, Belgium

§Department of Internal Medicine, Nephrology, Mannheim University Hospital, University of Heidelberg, Mannheim (formerly of Klinikum der Universität Regensburg, Regensburg), Germany

Renal Transplant Clinic, Hopital Erasme, Brussels, Belgium

Servicio de Nefrologia, Hospital Clinic, Barcelona, Spain

**Christiaan Barnard Memorial Hospital, Cape Town, South Africa

††Astellas Pharma Europe B.V., Leiderdorp, The Netherlands

‡‡Astellas Pharma Europe Limited, Staines, United Kingdom.

Correspondence: Nasrullah Undre, PhD, Astellas Pharma Europe Limited, Lovett House, Lovett Road, Staines, Middlesex TW18 3AZ, United Kingdom (e-mail: Nas.undre@eu.astellas.com).

The study and statistical analyses, and the editorial and project management services of ACUMED, involved in the preparation of this manuscript were supported by Astellas Pharma Europe Ltd, Staines, United Kingdom.

Statement of Interest: Z. Wlodarczyk has participated in clinical trials sponsored by Astellas, Novartis, and Roche; has received lecture fees from Astellas; and has served on advisory boards for Astellas and Wyeth. M. Ostrowski has participated in clinical trials sponsored by Astellas, Novartis, and Wyeth; has received lecture fees from Roche and travel grants from Astellas, Novartis, Roche, Wyeth; has received lecture fees from Roche and travel grants from Astellas, Novartis, Roche, and Wyeth. B.K. Krämer has received lecture fees and travel grants from Astellas Pharma Europe Ltd, BMS, Novartis, Roche, Teva, and Wyeth; grant support from Astellas Pharma Europe Ltd and Novartis; has served on advisory or safety boards for Astellas Pharma Europe Ltd, BMS, Novartis, Teva, and Wyeth; and has participated in clinical trials sponsored by Astellas Pharma Europe Ltd, BMS, Novartis, Roche, and Wyeth. F. Oppenheimer has participated in clinical trials sponsored by, and received consulting fees from Astellas, Novartis, Roche, and Wyeth. D. Miller has received travel grants from Astellas, Roche, Jansen Cilag, and Wyeth/Pfizer and has participated in clinical trials sponsored by Astellas, Wyeth/Pfizer and Boeringer Ingelheim. J. Dickinson and N. Undre are currently employees of Astellas. M. Mourad and D. Abramowicz have no conflicts of interest to declare.

Received June 23, 2011

Accepted January 26, 2012

© 2012 Lippincott Williams & Wilkins, Inc.