Ida Robertsen1, Anders Åsberg, Aleksander Olsen Ingerø, Nils Tore Vethe, Sara Bremer, Stein Bergan, Karsten Midtvedt. 1. 1 Department of Pharmaceutical Biosciences, School of Pharmacy, University of Oslo, Oslo, Norway. 2 Department of Transplant Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway. 3 Department of Pharmacology, Oslo University Hospital, Rikshospitalet, Oslo, Norway. 4 Department of Medical Biochemistry, Oslo University Hospital, Rikshospitalet, Oslo, Norway.
Abstract
BACKGROUND: Proper bioequivalence studies comparing original with generic immunosuppressive drugs in patients are limited, especially in the increasing population of elderly renal transplant recipients. We performed an open-label, single-center, prospective, randomized, cross-over study and compared steady-state pharmacokinetics (PK) of a generic tacrolimus (Tacni) formulation with the original (Prograf) in renal transplant recipients older than 60 years. METHODS:Twenty-eight patients, with a median age of 69 years (range, 60 to 78), were randomized at time of transplantation to receive original or generic tacrolimus, and 25 (21 men, 4 women) provided two evaluable 12-hr PK profiles. The PK investigations were performed in a stable phase approximately 6 and 8 weeks postengraftment. After the first PK investigation, tacrolimus formulations were switched (1:1 dose ratio). RESULTS:Generic tacrolimus did not meet the bioequivalence criteria; the area under the curve(0-12) ratio of generic-original tacrolimus formulation was 1.17 (90% confidence interval, 1.10-1.23) and the Cmax ratio was 1.49 (90% confidence interval, 1.35-1.65). The generic formulation also showed a shorter time to C(max) (T(max)) (P=0.04). Importantly, the lack of bioequivalence was not reflected in the standard monitoring parameter, trough concentrations (P=0.80). CONCLUSION:Generic tacrolimus (Tacni) was not found to be bioequivalent to the original formulation in elderly renal transplant recipients. The significantly higher systemic exposure of tacrolimus, despite similar trough concentrations, may in the long run increase the risk of adverse effects.
RCT Entities:
BACKGROUND: Proper bioequivalence studies comparing original with generic immunosuppressive drugs in patients are limited, especially in the increasing population of elderly renal transplant recipients. We performed an open-label, single-center, prospective, randomized, cross-over study and compared steady-state pharmacokinetics (PK) of a generic tacrolimus (Tacni) formulation with the original (Prograf) in renal transplant recipients older than 60 years. METHODS: Twenty-eight patients, with a median age of 69 years (range, 60 to 78), were randomized at time of transplantation to receive original or generic tacrolimus, and 25 (21 men, 4 women) provided two evaluable 12-hr PK profiles. The PK investigations were performed in a stable phase approximately 6 and 8 weeks postengraftment. After the first PK investigation, tacrolimus formulations were switched (1:1 dose ratio). RESULTS: Generic tacrolimus did not meet the bioequivalence criteria; the area under the curve(0-12) ratio of generic-original tacrolimus formulation was 1.17 (90% confidence interval, 1.10-1.23) and the Cmax ratio was 1.49 (90% confidence interval, 1.35-1.65). The generic formulation also showed a shorter time to C(max) (T(max)) (P=0.04). Importantly, the lack of bioequivalence was not reflected in the standard monitoring parameter, trough concentrations (P=0.80). CONCLUSION: Generic tacrolimus (Tacni) was not found to be bioequivalent to the original formulation in elderly renal transplant recipients. The significantly higher systemic exposure of tacrolimus, despite similar trough concentrations, may in the long run increase the risk of adverse effects.
Authors: Felix Krenzien; Abdallah ElKhal; Markus Quante; Hector Rodriguez Cetina Biefer; Uehara Hirofumi; Steven Gabardi; Stefan G Tullius Journal: Transplantation Date: 2015-11 Impact factor: 4.939
Authors: Rita R Alloway; Alexander A Vinks; Tsuyoshi Fukuda; Tomoyuki Mizuno; Eileen C King; Yuanshu Zou; Wenlei Jiang; E Steve Woodle; Simon Tremblay; Jelena Klawitter; Jost Klawitter; Uwe Christians Journal: PLoS Med Date: 2017-11-14 Impact factor: 11.069
Authors: Amber O Molnar; Dean Fergusson; Anne K Tsampalieros; Alexandria Bennett; Nicholas Fergusson; Timothy Ramsay; Greg A Knoll Journal: BMJ Date: 2015-06-22