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

被引：32

作者：

Kamar, Nassim ^{[1
,2
]}

Cassuto, Elisabeth ^{[3
]}

Piotti, Giovanni ^{[4
,5
]}

Govoni, Mirco ^{[5
]}

Ciurlia, Giorgia ^{[5
]}

Geraci, Silvia ^{[5
]}

Poli, Gianluigi ^{[5
]}

Nicolini, Gabriele ^{[5
]}

Mariat, Christophe ^{[6
]}

Essig, Marie ^{[7
]}

Malvezzi, Paolo ^{[8
]}

Le Meur, Yannick ^{[9
]}

Garrigue, Valerie ^{[10
]}

Del Bello, Arnaud ^{[1
,2
]}

Rostaing, Lionel ^{[8
]}

机构：

[1] Univ Paul Sabatier, CHU Rangueil, INSERM,U1043, IFR BMT,Dept Nephrol, Toulouse, France

[2] Univ Paul Sabatier, CHU Rangueil, INSERM,U1043, IFR BMT,Dept Organ Transplantat, Toulouse, France

[3] CHU Nice, Hop Pasteur 2, Unite Transplantat Renale, Nice, France

[4] Univ Hosp Parma, Kidney & Pancreas Transplantat Unit, I-43121 Parma, Italy

[5] Chiesi Farmaceut, Dept Clin Pharmacol, Global Clin Dev, Parma, Italy

[6] CHU St Etienne, Hop Nord, Ave Albert Raimond, St Priest En Jarez, France

[7] CHU Limoges, Nephrol Unit, 2 Ave Martin Luther King, Limoges, France

[8] CHU Grenoble Alpes, Serv Nephrol Dialyse Aphereses & Transplantat, Grenoble, France

[9] CHRU Brest, Hop Cavale Blanche, Serv Nephrol Transplantat Renale & Hemodialyse, Brest, France

[10] CHU Lapeyronie, Serv Nephrol Transplantat Dialyse Peritoneale, Montpellier, France

来源：

ADVANCES IN THERAPY | 2019年 / 36卷 / 02期

关键词：

Advagraf; De novo kidney transplantation; Envarsus; LCPT; Pharmacokinetics; PR Tac; Tacrolimus; TWICE-DAILY TACROLIMUS; LCP-TACRO; RENAL-TRANSPLANTATION; DOUBLE-BLIND; PHASE-III; GUIDELINES; REJECTION; INDEX;

D O I：

10.1007/s12325-018-0855-1

中图分类号：

R-3 [医学研究方法]; R3 [基础医学];

学科分类号：

1001 ;

摘要：

IntroductionDifferent prolonged-release formulations of tacrolimus are available. To date, the pharmacokinetic (PK) profile of LCP-tacrolimus (LCPT; Envarsus((R))) has not been compared with PR-Tac (Advagraf((R))) in de novo kidney transplant recipients. These profiles will guide clinical recommendations for the initiation and dose titration strategies of once-daily tacrolimus formulations.MethodsThis randomized, parallel-group, open-label, multicenter PK study randomized 75 de novo, adult, white kidney transplant recipients to LCPT 0.17mg/kg/day (n=37) or PR-Tac 0.20mg/kg/day (n=38) for 4 weeks. Dose adjustments were permitted to target a pre-defined therapeutic range based on measured trough blood concentrations.ResultsPK 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 similar to 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 similar to 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 (t(max)), lower maximum concentration (C-max) and a consistently lower daily dose (similar to 40% dose reduction with LCPT vs. PR-Tac by day 28). Safety profiles were similar.ConclusionIn 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 registrationRegistered at ClinicalTrials.gov; study number NCT02500212.FundingChiesi Farmaceutici S.p.A.

引用

页码：462 / 477

页数：16

共 31 条

[1]

Advagraf, SUMMARY PRODUCT CHAR

[2] Once- Versus Twice-Daily Tacrolimus Are the Formulations Truly Equivalent? [J].