BACKGROUND: Clinical data are lacking concerning therapeutic action and systemic exposure of tacrolimus (TAC) and everolimus (EVL) in a combined regimen in renal transplantation. METHODS: A prospective randomized phase II pharmacokinetic study was conducted comparing two fixed EVL dosages (0.75 mg two times per day (BID), group A, or 1.5 mg BID, group B) in combination with standard TAC dose. Complete 12-hr pharmacokinetic curves of both drugs were performed at days 4, 14, and 42 posttransplant. RESULTS: A higher TAC Cmin was observed with EVL dose of 0.75 mg BID (TAC 11.1+/-6.4 group A vs. 9.4+/-5.0 ng/mL group B, P=0.03), with equivalent TAC area under the curves (162+/-61 vs. 171+/-75). The exposure to TAC was lower in group B despite higher TAC doses were required to maintain target concentrations (day 14: 9.5 vs. 12.5 mg and day 42: 6 vs. 9 mg, P<0.05). Cmin-TAC/dose and area under the curve-TAC/dose ratios were significantly lower, from day 4 to day 42, in group B. Both groups achieved good graft function and acute rejection rate was similar (20% and 15%, respectively). CONCLUSIONS: We conclude that in adult renal transplant recipients, EVL significantly decreases TAC oral bioavailability in a dose-dependent manner. Doses higher than 1.5 mg BID would be probably needed for TAC-minimization strategies because 3 mg/day is not enough to achieve levels more than 3 ng/mL during the first 2 weeks. Therapeutic drug monitoring is mandatory to adjust the dose and prevent low TAC exposure. This regimen of low EVL exposure plus standard TAC exposure avoids wound healing problems with good efficacy.
RCT Entities:
BACKGROUND: Clinical data are lacking concerning therapeutic action and systemic exposure of tacrolimus (TAC) and everolimus (EVL) in a combined regimen in renal transplantation. METHODS: A prospective randomized phase II pharmacokinetic study was conducted comparing two fixed EVL dosages (0.75 mg two times per day (BID), group A, or 1.5 mg BID, group B) in combination with standard TAC dose. Complete 12-hr pharmacokinetic curves of both drugs were performed at days 4, 14, and 42 posttransplant. RESULTS: A higher TAC Cmin was observed with EVL dose of 0.75 mg BID (TAC 11.1+/-6.4 group A vs. 9.4+/-5.0 ng/mL group B, P=0.03), with equivalent TAC area under the curves (162+/-61 vs. 171+/-75). The exposure to TAC was lower in group B despite higher TAC doses were required to maintain target concentrations (day 14: 9.5 vs. 12.5 mg and day 42: 6 vs. 9 mg, P<0.05). Cmin-TAC/dose and area under the curve-TAC/dose ratios were significantly lower, from day 4 to day 42, in group B. Both groups achieved good graft function and acute rejection rate was similar (20% and 15%, respectively). CONCLUSIONS: We conclude that in adult renal transplant recipients, EVL significantly decreases TAC oral bioavailability in a dose-dependent manner. Doses higher than 1.5 mg BID would be probably needed for TAC-minimization strategies because 3 mg/day is not enough to achieve levels more than 3 ng/mL during the first 2 weeks. Therapeutic drug monitoring is mandatory to adjust the dose and prevent low TAC exposure. This regimen of low EVL exposure plus standard TAC exposure avoids wound healing problems with good efficacy.
Authors: Deirdre Hahn; Elisabeth M Hodson; Lorraine A Hamiwka; Vincent Ws Lee; Jeremy R Chapman; Jonathan C Craig; Angela C Webster Journal: Cochrane Database Syst Rev Date: 2019-12-16
Authors: Stephan W Hirt; Christoph Bara; Markus J Barten; Tobias Deuse; Andreas O Doesch; Ingo Kaczmarek; Uwe Schulz; Jörg Stypmann; Assad Haneya; Hans B Lehmkuhl Journal: J Transplant Date: 2013-12-05