Objectives: The once-daily prolonged-release formulation of tacrolimus (tacrolimus QD) is expected to demonstrate equivalent efficacy and safety to the twice-daily formulation (tacrolimus BID). We reviewed the 1-year outcomes of tacrolimus QD in de novo renal transplant.

Materials and Methods: We reviewed 50 de novo renal transplant patients assigned in a nonrandomized fashion to either tacrolimus QD (n = 23, historic control group) or tacrolimus BID (n = 27). Other immunosuppressive drugs used in both groups included mycophenolate mofetil, basiliximab, and steroids. We evaluated trough levels, required dosages, renal function, rejection rates, and episodes of infection within 1 year after transplant.

Results: Trough levels of both drugs varied during the perioperative periods, but subsequently stabilized in both groups. There was a tendency toward a slow elevation and a higher dosage requirement in the tacrolimus QD group, compared with the tacrolimus BID group in the early stages, though the required dosages decreased steadily. The rejection rate in the tacrolimus QD group was low, and only 1 patient experienced subclinical rejection. No severe infectious adverse events were observed.

Conclusions: Patients taking tacrolimus QD tended to have lower trough levels and require higher dosages than those taking tacrolimus BID during the early posttransplant period, though the differences decreased with increasing time after transplant. Tacrolimus QD can be administered with excellent efficacy and safety in de novo renal transplant recipients.

Key words : Prolonged-release, Trough levels, Renal function, Rejection rates

Introduction

Treatment with 4 immunosuppressive agents—tacrolimus, mycophenolate mofetil (MMF), basiliximab, and corticosteroids—is currently a common regimen for patients undergoing renal transplant, and this treatment has been shown to achieve excellent outcomes. A recently developed once-daily prolonged-release formulation of tacrolimus (tacrolimus QD) is expected to reduce patient nonadherence and to reduce calcineurin inhibitor (CNI) toxicity, resulting in improved long-term outcomes with similar efficacy and safety to twice-daily tacrolimus (tacrolimus BID).¹

The pharmacokinetics and pharmacodynamics of tacrolimus QD differ slightly from those of tacrolimus BID as a result of differences in the inactive ingredients included in the capsules. Some authors have previously reported on the use of tacrolimus QD in patients undergoing kidney transplant.^2-4 However, the optimal administration schedule for this agent in such patients has not been established. In the present article, we review 1-year follow-up results for 23 living-donor renal transplant recipients who were treated with tacrolimus QD in our clinic.

Materials and Methods

We retrospectively reviewed 23 living-donor renal transplant recipients who had received initial immunosuppression with tacrolimus QD (QD group) and 27 living-donor renal transplant recipients who had received tacrolimus BID (BID group). All protocols, experimental studies, and clinical trials involving human subjects were approved by the ethics committee of the institution before the study began, and that the protocols conformed to the ethical guidelines of the 1975 Helsinki Declaration. Written informed consent was obtained from every patient. The 2 groups were not contemporaneous and were divided historically. Patients in the QD group received transplants between March 2009 and December 2009, and patients in the BID group received transplants between January 2008 and February 2009. Patients who received preemptive transplants, repeat transplants, and patients who received ABO-incompatible and compatible transplants were included in both groups.

Immunosuppressive drugs were administered 1 week before transplant in ABO-compatible cases and 2 weeks before transplant in repeat transplanted and ABO-incompatible cases. The same immuno­suppressive drugs were prescribed for all patients in both the QD and BID groups: induction with basiliximab (20 mg daily at transplant and postoperative day 4) followed by MMF (1000 mg twice daily, tapered to 500 mg twice daily at about 3 months posttransplant), and corticosteroids (250 mg bolus injection intraoperatively, then 24 mg daily for first week, tapered to 4 mg daily by 1-month posttransplant). Levels of MMF were not monitored. Rituximab was administered 1 week before transplant in patients who received repeat transplants and ABO-incompatible transplants. Patients in the QD group received no continuous infusion of immunosuppressive agents throughout the course of the study.

Target tacrolimus trough levels in the QD group were as follows: 8 to 10 ng/mL by 2 weeks, 5 to 8 ng/mL by 2 months, and 3 to 5 ng/mL after 2 months. In the BID group, target tacrolimus trough levels were slightly higher: 10 to 12 ng/mL by 2 weeks, 6 to 10 ng/mL by 2 months, and 4 to 6 ng/mL after 2 months. In the BID group, an intravenous injection of tacrolimus was initiated intraoperatively, then tacrolimus BID was administered via the oral route the following morning. Tacrolimus was not injected in the QD group. Tacrolimus levels were measured by affinity column-mediated immunoassay, with daily dosages were adjusted as required to achieve target trough levels. Trough levels were measured daily throughout the 2 weeks after transplant, once a week, up to 3 months after transplant, then once every 2 weeks, up to 1 year after transplant. Tacrolimus dosages required to achieve trough levels were also evaluated (ie, trough level/QD or BID dosing). Graft function was assessed by measuring serum creatinine levels at the same time as trough levels of tacrolimus were measured.

The rate of biopsy-confirmed transplant rejection was determined. Biopsies were performed at 3 months and 1 year posttransplant as protocol biopsies, as well as at any time when rejection was suspected. All biopsies were evaluated and scored using the Banff 2007 classification system.⁵

Cytomegalovirus antigenemia and urine cytology were investigated (mainly to detect decoy cells) weekly until 3 months posttransplant, and monthly after 3 months posttransplant. If decoy cells were detected, the presence of BK virus in the blood was evaluated by polymerase chain reaction analysis.

Statistical analyses
Statistical values in the present study are expressed as means ± SD for each group. Data were analyzed using a 2-tailed t test (Excel 2003, Microsoft Corporation, Redmond, WA, USA). A value of P < .05 was considered statistically significant.

Results

Demographic characteristics of transplant recipients and donors in the QD and BID groups are shown in Table 1. The QD group contained 23 recipients with a mean age of 41.6 (15 females, 8 males) and BID group contained 27 recipients with a mean age of 36.0 (10 females, 17 males). There was no graft loss in any patient in either group.

Tacrolimus trough levels varied after transplant but stabilized within 1 week posttransplant in ABO-compatible transplant recipients (Figure 1) and ABO-incompatible or retransplant recipients (Figure 2) in both the QD and BID groups. At 3 months after transplant, tacrolimus trough levels were significantly lower in the QD group than in the BID group (4.66 ± 1.29 ng/mL vs 6.29 ± 1.81 ng/mL; P = .0015).

At 1 year after transplant, tacrolimus trough levels in the QD group tended to be lower than in the BID group (3.48 ± 0.82 ng/mL vs 3.97 ± 1.11 ng/mL; P = .0379). By contrast, the required daily tacrolimus dosage at 3 months after transplant was significantly higher in the QD group compared to the BID group (4.10 ± 1.46 mg daily vs 3.30 ± 1.22 mg daily). However, the required daily dosages at 1 year after transplant were almost identical between the QD and BID groups (2.60 ± 0.82 mg daily vs 2.57 ± 0.76 mg daily). In addition, the required dosages and trough levels tended to decrease in the QD group, in contrast to the BID group. Furthermore, MMF and steroid dosages in both groups decreased in accordance with our regimen from 3 months to 1 year after transplant, with no statistically significant differences between the groups.

Renal function in the patients was excellent, with no statistically significant differences between the 2 groups. The tacrolimus trough levels and required daily dosages in both groups at 3 months and 1 year after transplant are shown in Figure 3.

The transplant rejection rates within 1 year were 4.3% (1/23) in the QD group and 11.1% (3/27) in the BID group. One patient in the BID group had clinically significant symptoms of an elevated serum creatinine level at 9 months after transplant. The other patients had subclinical rejection indicated by protocol biopsy. All these patients were successfully treated with steroid pulse therapy. The presence of BK viremia was detected in 1 patient in each group, and cytomegalovirus disease was observed in 4 patients in the QD group and 7 patients in the BID group. None of these infections in either group were severe (Table 2).

Discussion

Tacrolimus is one of the most frequently used immunosuppressive agents. Tacrolimus BID has been used for many years with satisfactory results,6 and tacrolimus QD has recently been developed. Tacrolimus QD has been shown to have a similar efficacy and safety profile to tacrolimus BID in clinical trials.^{3, 7} The expected advantages of the once-daily formulation include decreased calcineurin inhibitor toxicity and improved quality of life for the recipient. However, little is known about this formulation, especially concerning its efficacy when used as a immunosuppressive drug in preemptive renal transplant.

Nielsen and associates reported that calcineurin activity was maintained for a long time after intake of tacrolimus BID.⁸ This finding indicates that, in contrast to the use cyclosporine, the ideal course of tacrolimus does not require the use of an intravenous transfusion to reach peak level.⁹ Thus, tacrolimus QD might be considered to be close to the ideal treatment.

We established a new regimen using tacrolimus QD in patients receiving preemptive renal transplant, and we examined the efficacy and safety of this new formulation, in comparison to the conventional twice-daily formulation, for 1 year after transplant.

In general, area under curve (AUC) is considered to be the most-reliable pharmacokinetics parameter for estimating the clinical efficacy of calcineurin inhibitors,¹⁰ although evidence is scarce.^11-13 In tacrolimus-treated renal transplant recipients, the trough level provides a reliable and easy-to-use means of estimating AUC.¹³ Therefore, we adjusted tacrolimus BID dosages on the basis of monitoring of trough levels. Like tacrolimus BID, trough levels of tacrolimus QD are well correlated with AUC.^{7, 14} In addition, blood concentrations of tacrolimus can be affected by bowel movements, food intake, and subtle time lags associated with blood drawing, especially during the perioperative period. Therefore, we did not evaluate AUC in the present study. Rather, we assumed that the trough level represented an adequate means of monitoring the effects of tacrolimus QD.

Determining the adequate trough level is difficult. During the 1990s—an era without MMF and basiliximab—low tacrolimus concentrations were used as an indication of increased risk of acute rejection.^{12, 15} However, quadruple immuno­suppression with tacrolimus, MMF, basiliximab, and steroids has since become a standard regimen, and lower trough levels of tacrolimus are now considered to be indicative of efficacy.^{6, 16-18} In our institution, the trough level has decreased in line with other institutions.

In the present study, the trough level in the QD group was decreased from an initial level of 10 ng/mL and a maintenance level of 4 to 5 ng/mL, compared with the BID group. Nevertheless, the rejection rate was lower in the QD group, and the infection rate also tended to be lower in this group, suggesting that the immunosuppressive condition in the QD group is appropriate. Although the present study was unable to confirm the reason for this finding, it is possible that maintenance of blood tacrolimus concentration with lower variation could have contributed to the favorable results.

Tacrolimus QD and tacrolimus BID are both formulations of tacrolimus, which is absorbed almost exclusively from the small intestine. The only difference between these drugs lies in the inactive ingredients included in the capsule, which result in slower absorption of tacrolimus QD. However, this extended-release time may be associated with difficulties in elevating the trough level to the target 10 ng/mL during the initial stage. Various factors, such as polymorphisms in the CYP3A locus,^{19, 20} dietary factors,²¹ and gastrointestinal motility²² have been reported to affect the absorption of tacrolimus.

Immunosuppressive treatment was initially started 1 week before transplant in ABO-compatible or preemptive cases, or 2 weeks before transplant in ABO-incompatible or retransplant cases. In the case of tacrolimus QD, target and steady trough levels could be achieved within 1 week from the start of administration. This early tacrolimus QD initiation enables the trough level to equilibrate, allowing for more-stable drug pharmacokinetics after transplant and avoiding unnecessary continuous injection. The easy adjustment of trough levels within 1 week of transplant contributes to the efficacy and safety of the QD formulation.

Patient nonadherence is an important factor that needs to be addressed. Although difficulties with the definition and measurement of nonadherence have led to widespread differences in reported frequencies, nonadherence has been reported to occur in 17% to 22% of patients in cross-sectional studies that defined nonadherence as missing, forgetting, or altering a dosage of medication at least once per month.^23-25 Many studies have suggested that nonadherence is common and a major cause of graft failure.^26-28

In the present study, we tried to determine the rate of nonadherence using a self-administered questionnaire. However, we concluded that the results of this questionnaire were unreliable. Thus, we were unable to determine if tacrolimus QD improved adherence, compared to tacrolimus BID. Nevertheless, improved adherence for a longer time can be expected to significantly improve graft survival.

The initial tacrolimus dosages required to achieve the target trough level in the QD group were higher than in the BID group,^{3, 7} which could be a cause of nonadherence.²⁹ However, the required tacrolimus dosages decreased over time, especially in the QD group, and the differences in trough and dosage between the groups was dramatically less at 1 year after transplant. The slightly higher dosages of QD were required only during the initial stage, and this disadvantage seems unlikely to outweigh the advantages of the once-daily formulation.

We can summarize the results of the use of the tacrolimus QD formulation as follows:

(1) Starting administration 1 week before transplant—or 2 weeks before transplant in cases of retransplants or ABO-incompatible transplants—is recommended;
(2) The target tacrolimus trough level is 10 ng/mL during the perioperative period, followed by a maintenance trough level of 3-4 ng/mL at 3 months after transplant;
(3) Trough levels provide an adequate surrogate marker for monitoring purposes;
(4) No continuous injection is needed throughout the course of transplant.

Additional long-term, comparative studies of tacrolimus QD and tacrolimus BID are needed to evaluate differences in the toxicity of calcineurin inhibitor, and to determine if the once-daily regimen improves patient adherence with consequent longer-term improvements. However, the results of the present study clearly demonstrate that tacrolimus QD is as safe and effective as tacrolimus BID in recipients of preemptive renal transplants.

References:

1. Kolonko A, Chudek J, Wiecek A. Improved kidney graft function after conversion from twice daily tacrolimus to a once daily prolonged-release formulation. Transplant Proc. 2011; 43(8):2950-2953.
   CrossRef - PubMed
2. Silva HT Jr, Yang HC, Abouljoud M, et al. One-year results with extended-release tacrolimus/MMF, tacrolimus/MMF and cyclosporine/MMF in de novo kidney transplant recipients. Am J Transplant. 2007;7(3):595-608.
   CrossRef - PubMed
3. Crespo M, Mir M, Marin M, et al. De novo kidney transplant recipients need higher doses of Advagraf compared with Prograf to get therapeutic levels. Transplant Proc. 2009;41(6):2115-2117.
   CrossRef - PubMed
4. Krämer BK, Charpentier B, Bäckman L, et al; Tacrolimus Prolonged Release Renal Study Group. Tacrolimus once daily (ADVAGRAF) versus twice daily (PROGRAF) in de novo renal transplantation: a randomized phase III study. Am J Transplant. 2010;10(12):2632-2643.
   CrossRef - PubMed
5. Cendales LC, Kanitakis J, Schneeberger S, et al. The Banff 2007 working classification of skin-containing composite tissue allograft pathology. Am J Transplant. 2008;8(7):1396-1400.
   CrossRef - PubMed
6. Ekberg H, Mamelok RD, Pearson TC, Vincenti F, Tedesco-Silva H, Daloze P. The challenge of achieving target drug concentrations in clinical trials: experience from the Symphony study. Transplantation. 2009;87(9):1360-1366.
   CrossRef - PubMed
7. Wlodarczyk Z, Squifflet JP, Ostrowski M, et al. Pharmacokinetics for once- versus twice-daily tacrolimus formulations in de novo kidney transplantation: a randomized, open-label trial. Am J Transplant. 2009;9(11):2505-2513.
   CrossRef - PubMed
8. Nielsen FT, Ottosen P, Starklint H, Dieperink H. Kidney function and morphology after short-term combination therapy with cyclosporine A, tacrolimus and sirolimus in the rat. Nephrol Dial Transplant. 2003;18(3):491-496.
   CrossRef - PubMed
9. Koefoed-Nielsen PB, Gesualdo MB, Poulsen JH, Jørgensen KA. Blood tacrolimus levels and calcineurin phosphatase activity early after renal transplantation. Am J Transplant. 2002;2(2):173-178.
   CrossRef - PubMed
10. Grevel J, Welsh MS, Kahan BD. Cyclosporine monitoring in renal transplantation: area under the curve monitoring is superior to trough-level monitoring. Ther Drug Monit. 1989;11(3):246-248.
    CrossRef - PubMed
11. Kuypers DR, Claes K, Evenepoel P, Maes B, Vanrenterghem Y. Clinical efficacy and toxicity profile of tacrolimus and mycophenolic acid in relation to combined long-term pharmacokinetics in de novo renal allograft recipients. Clin Pharmacol Ther. 2004;75(5):434-447.
    CrossRef - PubMed
12. Undre NA, van Hooff J, Christiaans M, et al. Low systemic exposure to tacrolimus correlates with acute rejection. Transplant Proc. 1999;31(1-2):296-298.
    CrossRef - PubMed
13. Jørgensen K, Povlsen J, Madsen S, et al. C2 (2-h) levels are not superior to trough levels as estimates of the area under the curve in tacrolimus-treated renal-transplant patients. Nephrol Dial Transplant. 2002;17(8):1487-1490.
    CrossRef - PubMed
14. Alloway R, Steinberg S, Khalil K, et al. Conversion of stable kidney transplant recipients from a twice daily Prograf-based regimen to a once daily modified release tacrolimus-based regimen. Transplant Proc. 2005;37(2):867-870.
    CrossRef - PubMed
15. Staatz C, Taylor P, Tett S. Low tacrolimus concentrations and increased risk of early acute rejection in adult renal transplantation. Nephrol Dial Transplant. 2001;16(9):1905-1909.
    CrossRef - PubMed
16. Cosio FG, Amer H, Grande JP, Larson TS, Stegall MD, Griffin MD. Comparison of low versus high tacrolimus levels in kidney transplantation: assessment of efficacy by protocol biopsies. Transplantation. 2007;83(4):411-416.
    CrossRef - PubMed
17. Gaston RS, Kaplan B, Shah T, et al. Fixed- or controlled-dose mycophenolate mofetil with standard- or reduced-dose calcineurin inhibitors: the Opticept trial. Am J Transplant. 2009;9(7):1607-1619.
    CrossRef - PubMed
18. Miura M, Harada H, Fukuzawa N, et al. Quadruple immunosuppression with basiliximab, tacrolimus, mycophenolate mofetil and prednisone is safe and effective for renal transplantation. Clin Transplant. 2005;19(suppl 14):54-58.
    CrossRef - PubMed
19. Satoh S, Saito M, Inoue T, et al. CYP3A5 *1 allele associated with tacrolimus trough concentrations but not subclinical acute rejection or chronic allograft nephropathy in Japanese renal transplant recipients. Eur J Clin Pharmacol. 2009;65(5):473-481.
    CrossRef - PubMed
20. Tsuchiya N, Satoh S, Tada H, et al. Influence of CYP3A5 and MDR1 (ABCB1) polymorphisms on the pharmacokinetics of tacrolimus in renal transplant recipients. Transplantation. 2004;78(8):1182-1187.
    CrossRef - PubMed
21. Bekersky I, Dressler D, Mekki QA. Effect of low- and high-fat meals on tacrolimus absorption following 5 mg single oral doses to healthy human subjects. J Clin Pharmacol. 2001;41(2):176-182.
    CrossRef - PubMed
22. Bekersky I, Dressler D, Mekki Q. Effect of time of meal consumption on bioavailability of a single oral 5 mg tacrolimus dose. J Clin Pharmacol. 2001;41(3):289-297.
    CrossRef - PubMed
23. Didlake RH, Dreyfus K, Kerman RH, Van Buren CT, Kahan BD. Patient noncompliance: a major cause of late graft failure in cyclosporine-treated renal transplants. Transplant Proc. 1988;20(3 suppl 3):63-69.
    PubMed
24. Sketris I, Waite N, Grobler K, West M, Gerus S. Factors affecting compliance with cyclosporine in adult renal transplant patients. Transplant Proc. 1994;26(5):2538-2541.
    PubMed
25. Teixeira de Barros C, Cabrita J. Noncompliance with immunosuppressive therapy: prevalence and determinants. Transplant Proc. 2000;32(8):2633.
    CrossRef - PubMed
26. Butler JA, Roderick P, Mullee M, Mason JC, Peveler RC. Frequency and impact of nonadherence to immunosuppressants after renal transplantation: a systematic review. Transplantation. 2004;77(5):769-776.
    CrossRef - PubMed
27. Weng FL, Israni AK, Joffe MM, et al. Race and electronically measured adherence to immunosuppressive medications after deceased donor renal transplantation. J Am Soc Nephrol. 2005;16(6):1839-1848.
    CrossRef - PubMed
28. Ichimaru N, Kakuta Y, Abe T, et al. Treatment adherence in renal transplant recipients: a questionnaire survey on immunosuppressants. Transplant Proc. 2008;40(5):1362-1365.
    CrossRef - PubMed
29. Laederach-Hofmann K, Bunzel B. Noncompliance in organ transplant recipients: a literature review. Gen Hosp Psychiatry. 2000;22(6):412-424.
    CrossRef - PubMed