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Randomized Controlled Trial
. 2019 Feb;36(2):462-477.
doi: 10.1007/s12325-018-0855-1. Epub 2018 Dec 14.

Pharmacokinetics of Prolonged-Release Once-Daily Formulations of Tacrolimus in De Novo Kidney Transplant Recipients: A Randomized, Parallel-Group, Open-Label, Multicenter Study

Nassim Kamar  1 , Elisabeth Cassuto  2 , Giovanni Piotti  3   4 , Mirco Govoni  5 , Giorgia Ciurlia  4 , Silvia Geraci  4 , Gianluigi Poli  4 , Gabriele Nicolini  4 , Christophe Mariat  6 , Marie Essig  7 , Paolo Malvezzi  8 , Yannick Le Meur  9 , Valerie Garrigue  10 , Arnaud Del Bello  1 , Lionel Rostaing  8
Affiliations
Randomized Controlled Trial

Pharmacokinetics of Prolonged-Release Once-Daily Formulations of Tacrolimus in De Novo Kidney Transplant Recipients: A Randomized, Parallel-Group, Open-Label, Multicenter Study

Nassim Kamar et al. Adv Ther. 2019 Feb.

Abstract

Introduction: Different prolonged-release formulations of tacrolimus are available. To date, the pharmacokinetic (PK) profile of LCP-tacrolimus (LCPT; Envarsus®) has not been compared with PR-Tac (Advagraf®) in de novo kidney transplant recipients. These profiles will guide clinical recommendations for the initiation and dose titration strategies of once-daily tacrolimus formulations.

Methods: This randomized, parallel-group, open-label, multicenter PK study randomized 75 de novo, adult, white kidney transplant recipients to LCPT 0.17 mg/kg/day (n = 37) or PR-Tac 0.20 mg/kg/day (n = 38) for 4 weeks. Dose adjustments were permitted to target a pre-defined therapeutic range based on measured trough blood concentrations.

Results: PK analysis (days 1, 3, 7 and 14) included 68 patients (LCPT, n = 33; PR-Tac, n = 35). Similar proportions of patients were within the pre-defined therapeutic tacrolimus trough blood concentration range, with < 12% in each group having below-target trough levels over the study period. LCPT demonstrated ~ 30% greater relative bioavailability [LCPT/PR-Tac adjusted geometric mean ratio: day 3, 1.32 (p = 0.007); day 7, 1.25 (p = 0.051); day 14, 1.43 (p = 0.002)] and ~ 30% lower peak-to-trough percentage fluctuation of blood concentration [LCPT/PR-Tac adjusted geometric mean ratio: day 3, 0.70 (p < 0.001); day 7, 0.68 (p < 0.001); day 14, 0.73 (p = 0.004)] in addition to longer time to maximum blood concentration (tmax), lower maximum concentration (Cmax) and a consistently lower daily dose (~ 40% dose reduction with LCPT vs. PR-Tac by day 28). Safety profiles were similar.

Conclusion: In de novo kidney transplant recipients, prolonged-release formulations of tacrolimus can reach therapeutic concentrations in the immediate post-transplant period. LCPT has greater relative bioavailability and lower peak-to-trough fluctuation compared with PR-Tac.

Trial registration: Registered at ClinicalTrials.gov; study number NCT02500212.

Funding: Chiesi Farmaceutici S.p.A.

Keywords: Advagraf; De novo kidney transplantation; Envarsus; LCPT; PR Tac; Pharmacokinetics; Tacrolimus.

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Figures

Fig. 1
Fig. 1
Study design
Fig. 2
Fig. 2
Patient disposition. *Reasons for not receiving the allocated LCPT treatment (and being excluded from the safety and PK analysis populations) were: transplantation not performed (n = 2); patient did not meet inclusion/exclusion criteria (n = 1); study logistical issues (n = 1). Reasons for not receiving the allocated PR-Tac treatment (and being excluded from the safety and PK analysis populations) were: transplantation not performed (n = 1); patient withdrew consent (n = 1). ‡Death due to coronary artery thrombosis. †Discontinuation due to vascular graft thrombosis. §Excluded from the PK analysis for receiving only one dose of PR-Tac following the diagnosis of vascular graft thrombosis on study day 1. AE adverse event, LCPT LCP-tacrolimus, PK pharmacokinetic, PR prolonged release, CI confidence interval. Solid line represents 100%
Fig. 3
Fig. 3
Between treatment group PK comparisons: a analysis of  % peak-to-trough fluctuation (PK population). b Analysis of dose-normalized AUC0–24h (PK population)
Fig. 4
Fig. 4
Concentration-time plots: a day 1; b day 3; c day 7; d day 14
Fig. 5
Fig. 5
Daily dose of tacrolimus: a mean daily dose; b weight-adjusted mean daily dose
Fig. 6
Fig. 6
Mean serum creatinine (a) and mean eGFR (b)
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References

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