Pharmacokinetics for Once- Versus Twice-Daily Tacrolimus Formulations in De Novo Kidney Transplantation: A Randomized, Open-Label Trial

Abstract

Tacrolimus, a cornerstone immunosuppressant, is widely available as a twice-daily formulation (Tacrolimus BID). A once-daily prolonged-release formulation (Tacrolimus QD) has been developed that may improve adherence and impart long-lasting graft protection. This study compared the pharmacokinetics (PK) of tacrolimus in de novo kidney transplant patients treated with Tacrolimus QD or Tacrolimus BID. A 6-week, open-label, randomized comparative study was conducted in centers in Europe and Australia. Eligible patients received Tacrolimus QD or Tacrolimus BID. PK profiles were obtained following the first tacrolimus dose (day 1), and twice under steady-state conditions. As secondary objectives, efficacy and safety parameters were also evaluated. Sixty-six patients completed all PK profiles (34 Tacrolimus QD, 32 Tacrolimus BID). Mean AUC 0-24 of tacrolimus on day 1 was approximately 30% lower for Tacrolimus QD than Tacrolimus BID (232 and 361 ng.h/mL, respectively), but was comparable by day 4. There was a good correlation and a similar relationship between AUC 0-24 and C min for both formulations. Efficacy and safety data were also comparable over the 6-week period. Tacrolimus QD can be administered once daily in the morning on the basis of the same systemic exposure and therapeutic drug monitoring concept as Tacrolimus BID.

Immunosuppressive therapy for kidney transplantation in adults: a systematic review and economic model

“…The method of concealment of allocation was clearly reported in 12 trials (two induction studies, 97,128 nine maintenance studies, 58,114,129,130,133,140,147,150,152 and one study 136 of both induction and maintenance treatment). Fifty-four trials 51,[72][73][74][76][77][78][79][81][82][83][84][85][87][88][89][91][92][93]95,96,[98][99][100][102][103][104][105][106][108][109][110][111][112][113][115][116][117][118][119][120]124,…”

“…Nine trials (eight maintenance studies 88,89,92,[110][111][112]122,148 and one study 148 of both induction and maintenance) reported significant baseline between-group differences for key factors, including PRA grade, number of previous transplants, patient age, pretransplant diabetes mellitus, HLA mismatches and ECD donor kidneys. A further six maintenance studies 91,101,130,133,140,155 were rated as 'partial' because they reported a baseline difference in patient sex.…”

“…Five induction studies, 87,96,98,128,137 47 maintenance studies 51,59,76,[78][79][80][82][83][84]86,88,[92][93][94]103,[105][106][107][108]111,113,116,118,125,126,[129][130][131][132][133][134][135][138][139][140][141][142][144][145][146][147][148][149][151][152][153]155 and both of the studies of induction and maintenance treatment 123,148 did not blind participants to treatment allocation.…”

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“…Most previous pharmacokinetics studies comparing twice-daily and once-daily tacrolimus in de novo transplant recipients have reported that, after once-daily tacrolimus administration, C min values are reduced in the immediate posttransplant period and higher doses of the drug are required to maintain target concentrations. 9,24,25 A previous multicenter comparison of the safety and efficacy of tacrolimus administered once-versus twice-daily to de novo LDLT recipients also demonstrated lower C min values and a higher dose requirement for once daily tacrolimus than for twice-daily tacrolimus when normalized to mr doses of tacrolimus (unpublished data). Here, a higher dose of once-daily tacrolimus was required to maintain target concentrations during the posttransplant period, especially immediately after the conversion from intravenous to oral administration of the drug.…”

“…6 However, clinical evidence from liver, kidney, and heart transplant recipients during clinical trials indicated that there were no marked differences between the efficacy and safety profiles of the 2 formulations. [7][8][9] The pharmacokinetics characteristics of once-daily tacrolimus in livingdonor liver transplant (LDLT) recipients have not yet been assessed; therefore, the objective of this study was to examine the pharmacokinetics properties of once-daily tacrolimus, both after the first oral dose and under steady-state conditions (before the 10th oral dose), in patients undergoing de novo LDLT.…”