Pharmacokinetics for once-daily versus twice-daily tacrolimus formulations in de novo liver transplantation: A randomized, open-label trial

Abstract

Tacrolimus, a cornerstone immunosuppressant, is available as a twice-daily formulation (tacrolimus bid). A once-daily prolonged-release formulation (tacrolimus qd) has been developed. This 6-week, randomized, phase 2, multicenter, open-label, prospective trial in primary liver transplant recipients investigated and compared the pharmacokinetics (PK) of tacrolimus for qd and bid formulations. All patients received tacrolimus-based immunosuppression (tacrolimus qd, n ¼ 67; bid, n ¼ 62). PK data were available for 77 patients (tacrolimus qd, n ¼ 45; bid, n ¼ 32). Tacrolimus area under the curve (AUC) from 0 to 24 hours (AUC 0-24 ) at equivalent doses was approximately 50% lower for tacrolimus qd than for bid on day 1 (146 versus 264 ngÁh/mL, respectively), but by day 14 was comparable between treatments (324 and 287 ngÁh/mL, respectively) with higher tacrolimus qd doses. There was a strong correlation between AUC 0-24 and concentration at 24 hours for tacrolimus qd and bid (r ¼ 0.92 and r ¼ 0.76, respectively). Furthermore, the relationship between these 2 parameters (ie, the slope of the line) was also similar for the 2 formulations. Efficacy endpoints were comparable for both formulations at 6 weeks with Abbreviations: AE, adverse event; AUC 0-24 , area under the curve from 0 to 24 hours; AZA, azathioprine; bid, twice daily; BPAR, biopsy-proven acute rejection; C 24 , concentration at 24 hours; C max , maximum concentration; C min , minimum blood concentration; MMF, mycophenolate mofetil; NEC, not elsewhere classified; PK, pharmacokinetics; qd, once daily; SD, standard deviation; T max , time to maximum concentration. This study and statistical analyses, and the editorial and project management services of Acumed involved in the preparation of this manuscript, were supported by Astellas Pharma Europe, Ltd., Staines, UK. L. Fischer, B. Gridelli, A. Roy, A. Vitale, A. Valdivieso, E. Varo, D. Seehofer, B. Ericzon, and K. Boudjema have declared no conflicts of interest. P. Trunečka has acted as study investigator and advisory board member for Astellas and has received speaker's fees. S. Lynch has received honoraria for chairing and speaking at international meetings for Astellas and JanssenCilag,

Pharmacokinetics of tacrolimus converted from twice-daily formulation to once-daily formulation in Chinese stable liver transplant recipients

“…Similar to other reports [9][10][11][12][13] , the present study also showed that there was a good correlation between AUC 0-24 and C 24 for both IR and MR tacrolimus. The fact that the slope of the line best fit was similar for both formulations indicates that the same therapeutic drug monitoring for IR tacrolimus could be applied to MR tacrolimus.…”

“…Before our study, a set of clinical trials had been conducted to compare the PK profi les of tacrolimus between IR and MR formulations [9][10][11][12][13] . The clinical trial in de novo liver transplant patients showed that the systemic exposure AUC 0-24 on d 1 was approximately 50% lower for MR tacrolimus than for IR tacrolimus at equivalent doses, whereas values at steady state (d 14 and w 6) were similar for both formulations [13] .…”

“…The clinical trial in de novo liver transplant patients showed that the systemic exposure AUC 0-24 on d 1 was approximately 50% lower for MR tacrolimus than for IR tacrolimus at equivalent doses, whereas values at steady state (d 14 and w 6) were similar for both formulations [13] . The conversion study in stable liver transplant patients showed that the AUC 0-24 at steady state for MR tacrolimus once daily was equivalent to taking IR tacrolimus twice a day, but on average an 11% lower AUC 0-24 was found after a mg-for-mg dose conversion [9] .…”

“…This formulation, known commercially as Advagraf, has been approved in more than 30 countries and regions as of 2010. The pharmacokinetics (PK) of tacrolimus have been compared between MR and IR formulations in stable kidney, liver, and heart transplant patients, and in de novo kidney and liver transplant recipients [9][10][11][12][13] . However, there is few clinical data on Chinese patients.…”

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“…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.…”