Tacrolimus QD Research Articles

Once-daily prolonged-release tacrolimus versus twice-daily tacrolimus in liver transplantation

ObjectiveFor patients who have received a kidney transplant, studies have shown that once-daily prolonged-release tacrolimus (TAC) has similar efficacy and safety to standard twice-daily dosing. The purpose of this study was to perform a meta-analysis to compare the effectiveness and safety of daily TAC (TAC qd) versus standard twice-daily TAC (TAC bid) administration in liver transplantation (LT). DesignMeta-analysis. Setting and participantsWe systematically searched the PubMed/MEDLINE, Web of Science, and Cochrane Library databases for studies comparing outcomes of LT patients who received TAC qd versus TAC bid. Outcome measuresResults were reported as odds ratios (ORs) with 95% CIs. ResultsSix studies, which included 5179 LT recipients (TAC qd = 951; TAC bid = 4228) were included in the analysis. The TAC qd group had a low 1-year graft loss rate (OR 0.70 [95% CI 0.54–0.91], P = 0.008) and lower rate of biopsy-proven acute rejection (BPAR) at 90 days (OR 0.46 [95% CI 0.24–0.89], P = 0.02) compared with the TAC bid group. There was no significant difference in 1-year mortality or the incidence of adverse events after LT between the 2 groups. ConclusionsCurrent evidence suggests that TAC qd is safe and effective for LT patients during the first year after transplantation. Longer-term follow-up studies are necessary to determine if TAC qd is safe and effective beyond the first year after LT.

Factors associated with the variability of calcineurin inhibitor blood levels in kidney recipients grafted for more than 1year.

The study of calcineurin inhibitor (CNI) blood level variability to evaluate adherence in transplantation has improved over the years. The aim of our study was to assess factors associated with this variability using the coefficient of variation (CV). A cross-sectional sample of kidney recipients grafted for more than 1year was recruited. We recorded clinical data, data from a clinical pharmacist interview and from six questionnaires measuring adherence, satisfaction, behaviours, beliefs, perception of the illness and social vulnerability. A total of 408 recipients were enrolled (61.2% male, mean age 54) and divided into two groups: low variability CV<30% (n=302), high variability CV≥30% (n=106). In univariate analysis, hospital-home distance, cyclosporine, time since transplantation and presence of discrepancies in drug regimen were associated with a greater risk of CV≥30%. In contrast, tacrolimus QD conferred a lower risk of CV≥30%. In multivariate analysis, only the presence of discrepancies remained significant: (OR 3.2 [1.21-9.01]; P=0.022). Discrepancies in drug regimen appear as the main risk factor associated with CNI blood variability. The clinical pharmacist's input is an accurate and simple way of detecting non-adherence which is not revealed in self-report questionnaires.

Ten-years data of the first European clinical experience with once-daily tacrolimus extended release formulation in renal transplant recipients

Background: Clinical data about long-term use of tacrolimus QD are lacking. Methods: Ten-years data were collected from 37 renal transplant recipients participating in a Tacrolimus BID (Prograf®) to QD (Advagraf®) conversion study. They were converted at a median of 4.1 years post-transplant (range 1.5-11.4) with a stable renal function (serum creatinine 20% had an immunological or unknown cause of renal failure. Conclusion: Patients on tacrolimus QD have excellent 10-year renal function, patient - and graft survival.

Advagraf(®) , a once-daily prolonged release tacrolimus formulation, in kidney transplantation: literature review and guidelines from a panel of experts.

The efficacy and safety of tacrolimus twice-a-day (BID) and once-a-day (QD) formulations are similar. However, the available information regarding the initiation and management of tacrolimus QD is sparse and practical information is lacking. A panel of French experts extensively reviewed the available literature on tacrolimus pharmacokinetics, clinical efficacy, and safety in kidney transplantation and, based on their own day-to-day experience, provided the practitioners with practical guidelines for the daily use and management of tacrolimus QD in de novo initiation or early conversion.

Renal Function Outcomes With Tacrolimus QD After De Novo Liver Transplantation for Different Primary Diseases: Ad Hoc Analysis From The DIAMOND Randomized, Controlled Trial.

Renal Function Outcomes With Tacrolimus QD After De Novo Liver Transplantation for Different Primary Diseases: Ad Hoc Analysis From The DIAMOND Randomized, Controlled Trial.

Observational Study of a Large Cohort of Liver and Kidney Transplanted Patients Converted to Tacrolimus QD (ADVAGRAF®): Acceptance and Compliance to ADVAGRAF®.

Observational Study of a Large Cohort of Liver and Kidney Transplanted Patients Converted to Tacrolimus QD (ADVAGRAF®): Acceptance and Compliance to ADVAGRAF®.

OSAKA Trial

BackgroundThe once-daily (QD), prolonged-release formulation of tacrolimus has been shown to improve adherence versus twice-daily (BD) tacrolimus. Treatment nonadherence in transplant recipients has been associated with poor graft outcomes.MethodsThis open-label, parallel-group study randomized adults with end-stage renal disease undergoing primary kidney transplantation or retransplantation to an initial dose of tacrolimus BD 0.2 mg/kg per day (Arm 1; n=309), QD 0.2 mg/kg per day (Arm 2; n=302), QD 0.3 mg/kg per day (Arm 3; n=304) all with mycophenolate mofetil and corticosteroids (tapered) over 24 weeks, or tacrolimus QD 0.2 mg/kg per day with mycophenolate mofetil, basiliximab, and corticosteroids given only perioperatively (Arm 4; n=283). The primary composite endpoint (efficacy failure; per protocol set) was defined as graft loss, biopsy-confirmed acute rejection, or graft dysfunction at week 24. Graft dysfunction was defined as estimated glomerular filtration rate Modification of Diet in Renal Disease-4 formula of less than 40 mL/min/1.73 m2. The prespecified noninferiority margin was 12.5%.ResultsThe per protocol set included 976 patients: 237, 263, 246, and 230 patients in Arms 1 to 4, respectively. Noninferiority of the composite endpoint was demonstrated for Arm 2 versus Arm 1; Kaplan–Meier estimates of efficacy failure were 42.2% and 40.6%, respectively (difference, −1.6%; 95% confidence interval [CI], −12.2% to 9.0%). Noninferiority to Arm 1 was not confirmed for Arm 3 (difference, −3.5%; 95% CI, −13.6% to 6.6%) or Arm 4 (difference, −7.1%; 95% CI, −16.1% to 1.9%). Graft dysfunction (estimated glomerular filtration rate <40 mL/min/1.73 m2) was the main determinant of composite-endpoint efficacy failure across all arms.ConclusionsIn patients representative of the European kidney transplant population, tacrolimus QD-based immunosuppression (0.2 mg/kg/day), without induction, showed similar efficacy to 0.2 mg/kg per day tacrolimus BD.

Comparison of Pharmacokinetics and Pathology for Low-Dose Tacrolimus Once-Daily and Twice-Daily in Living Kidney Transplantation

A prolonged-release formulation of tacrolimus (Tacrolimus QD) was developed to allow once-daily dosing and to have similar safety and efficacy profiles to twice-daily tacrolimus (Tacrolimus BID). This study compared the pharmacokinetics (PK) and renal pathology by protocol biopsy in de novo living kidney transplant recipients treated with either low-dose Tacrolimus QD or Tacrolimus BID. Between November 2009 and January 2011, 102 consecutive adult patients were randomized to receive either low-dose Tacrolimus QD or Tacrolimus BID. All patients underwent PK study and protocol biopsy on postoperative day 14. Additional protocol biopsies were performed between 6 and 12 months after renal transplantation. During the 1-year follow up, the incidence of biopsy-proven acute rejection and toxic tubulopathy was low and similar in both groups. Twenty-four hours area under the curve (AUC0-24) was not different in both groups (285 ± 78.7 and 281 ± 62.4 ng hr/mL in Tacrolimus QD and Tacrolimus BID, respectively). C0 was well correlated with AUC0-24 in both groups and AUC0-24 between 260 and 280 in the Tacrolimus QD group was achieved by 6 to 8 ng/mL of C0. Acute nephrotoxicity was less than 10% in both groups without any clinical manifestation. Clinical efficacy, safety, and PK profile of Tacrolimus QD is same as those of Tacrolimus BID.

Pharmaceutical and genetic determinants for interindividual differences of tacrolimus bioavailability in renal transplant recipients

The pharmacokinetics of orally administered immediate-release, twice-daily (BID) and modified-release, once-daily (QD) formulations of tacrolimus have high interindividual variability. We investigated factors affecting interindividual variability of tacrolimus bioavailability in renal transplant patients. Ninety-seven Japanese renal transplant patients (47 patients on tacrolimus BID and 50 patients on tacrolimus QD) were enrolled in this study. The tacrolimus absolute bioavailability was calculated using the area under the concentration-time curve from 0 to 24 h (AUC0-24) after continuous intravenous infusion and oral formulations of tacrolimus in the same recipient. The median (quartile 1-quartile 3) tacrolimus relative bioavailability for recipients with the CYP3A5*1 or CYP3A5*3/*3 alleles was significantly lower for the tacrolimus QD group [9.1 % (6.3-10.7 %) and 15.4 % (11.5-18.7 %), respectively] than for the tacrolimus BID group [12.6 % (9.9-14.2 %) and 19.3 % (16.5-24.8 %), respectively] (P = 0.004 and 0.028, respectively). Consequently, tacrolimus absolute bioavailability was lowest for recipients with the CYP3A5*1 allele taking tacrolimus QD. The CYP3A5 polymorphism had no impact on the dose-adjusted AUC0-24 of tacrolimus in patients on continuous intravenous infusion (P = 0.906). The larger interindividual variability of tacrolimus bioavailability for oral formulations appears to be due to the effects of the CYP3A5 polymorphism and the tacrolimus oral formulation. These factors should therefore be taken into account when determining individualized tacrolimus dosing.

Conversion from twice daily tacrolimus to once daily tacrolimus in long-term stable liver transplant recipients: A single-center experience with 394 patients

After organ transplantation, strategies for simplifying the therapeutic regimen may improve adherence and prevent acute organ rejection and/or late graft loss. The aim of the present study was to evaluate the safety and efficacy of conversion from a tacrolimus (TAC) twice daily (bid) formulation to a once daily (qd) formulation in a large cohort of adult liver transplantation (LT) patients. This retrospective, observational, single-center study included 394 LT patients with at least 6 months' posttransplant follow-up and no rejection episodes in the last 3 months. The conversion from a bid formulation to a qd formulation was based on a 1:1 ratio. The mean age at the time of conversion was 53 years (range = 18-72 years); 66% were men. The main indication for LT was alcoholic cirrhosis (41%). The mean conversion time after LT was 74 months (range = 6-218 months). The mean serum TAC trough level decreased after conversion (6.1 ± 5.6 ng/mL before conversion versus 4.9 ± 2.5 ng/mL after conversion, P < 0.05). After a mean follow-up of 24 months after conversion, 6 patients had converted to cyclosporine, 14 patients had stopped all calcineurin inhibitors, 16 patients had returned to TAC bid, and 358 patients were still on TAC qd. Acute rejection episodes were observed in 7 patients. In conclusion, the results of our experience indicate that the conversion from a TAC bid formulation to a qd formulation is a safe and effective strategy for the management of stable LT patients.

One-Year Follow-Up of Treatment With Once-Daily Tacrolimus in De Novo Renal Transplant

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. 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. 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. 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.

Tacrolimus QD Is Equivalent to Tacrolimus BID in All Measures of Clinical Efficacy

Introduction: Two large prospective studies of tacrolimus prolonged release (QD) versus tacrolimus immediate release (BID) were performed in de novo renal transplantation. Both studies were designed as non-inferiority trials of tacrolimus QD and tacrolimus BID in combination with mycophenolate mofetil and low-dose corticosteroids. The first study (12-03) was a double-blind, double-dummy, randomized controlled trial, and the second study (OSAKA) was an open-label, parallel-group trial. In these studies, efficacy was assessed after 6 months (24 weeks) in terms of biopsy-confirmed acute rejection rates (BCAR; Study 12-03) and a composite endpoint following EMA guidelines (graft loss, BCAR, renal dysfunction at the end-of-study visit; Study OSAKA). The present analyses investigate different efficacy parameters on the basis of a combined database. Methods: Data from both studies (full analysis sets) were combined to one common database. In these studies, patient and graft survival, BCAR (local pathology), and renal function (eGFR; MDRD4-algorithm) data at end-of-study, follow-up or last visit were assessed. For the present analyses, data were collected up to the formal end-of-study visit or the follow-up visit. In these analyses, evaluation was performed according to the single endpoint of BCAR, the US FDA composite endpoint (graft loss, BCAR, loss to follow-up) and the EMA composite endpoint. Renal dysfunction was defined as eGFR < 40mL/min/1.73m2. The 95% confidence intervals were calculated taking a 10% margin for non-inferiority. Results: The combined database included 633 patients receiving tacrolimus QD (331 patients from study 12-03, 302 from OSAKA) and 645 patients receiving tacrolimus BID (336 patients from 12-03, 309 from OSAKA). Treatment group demographics were well balanced with the majority of organs from deceased male donors aged < 60 years. The rate of study completers was 78.5% (497/633) in the tacrolimus QD group and 83.1% (536/645) in the tacrolimus BID group. The incidence of BCAR was 13.9% versus 14.1% in the tacrolimus QD and BID groups, respectively. The US FDA composite endpoint was reached by 21.5% of tacrolimus QD-treated and 19.8% of tacrolimus BID-treated patients, and the EMA composite endpoint was reached by 40.3% of patients in the tacrolimus QD group and 38.3% in the tacrolimus BID group. Differences in incidence were between -0.2% and +2.0% and the 95% confidence intervals were between -4.0% and +7.4% (Table).Conclusions: Results from a combined database including data from a double-blind study and data from an open-label study reveal that standard efficacy endpoints (BCAR, US FDA and EMA composite endpoints) demonstrate non-inferiority of tacrolimus prolonged-release versus tacrolimus immediate-release treatment.

How Safe Is Conversion from Twice-Daily Tacrolimus to Once-Daily Prolonged Formulation? Single Centre Experience

Introduction: The calcineurin inhibitor tacrolimus, is widely available as a twice- daily formulation (Tacrolimus BID). A once- daily prolonged- release formulation (Tacrolimus QD) has been developed to improve the adherence and provide the long- lasting graft protection. Methods: The objective of this retrospective single centre study was to analyze 589 kidney transplant recipients who underwent conversion from Tacrolimus BID to Tacrolimus QD in 11/2007-09/2010. The aim of the study was to compare the renal function in patients before and after conversion and to determine the incidence of acute rejection after switch to Tacrolimus QD during the 12 month follow-up. The rejection was histologically verified in indication biopsies performed due to graft function deterioration. Maintenance immunossuppresive therapy was based on tacrolimus, mycophenolate mophetil and corticosteroids in majority of patients. Results: The median time of conversion was 4.1 years after transplantation. We observed no graft function deterioration (eGFR-MDRD before 52.8 ± 17.4 ml/min/1.73m2 vs. after 46.2 ± 19.2 ml/min/1.73m2, p = n.s.,) nor the significant change in Tacrolimus trough level (5.07 ± 1.22 μg/L vs. 4.93 ± 1.01 μg/L, p = n.s.) after switch to Tacrolimus BID. Rejection episodes occurred at median time 10 months after conversion. We assessed the rejections with regard to time to drug switch and observed higher rate of late rejection (acute rejection 2 %, chronic rejection 1.6 %) compared to early rejections within 3 months after conversion (0.5 % acute and 0.3 % chronic rejection). No new-onset of diabetes mellitus after transplantation was recorded. 1- year graft survival was 97 %. 49 out of 589 patients (8 %) didn't finish the follow-up due to various reasons (graft failure, intolerance of Tacrolimus QD, version to mTOR inhibitors due to malignancy or severe arteriolopathy). Conclusions: No differences in renal function, tacrolimus level was found after conversion from Tacrolimus BID to Tacrolimus QD and incidence of acute rejection was low. These findings suggest that a once-daily morning dosing regimen maximizes the potential for adherence and may improve the long- term outcomes.

Tacrolimus Pharmacokinetics of Once- Versus Twice-Daily Formulations in De Novo Kidney Transplantation

Tacrolimus is a well-established immunosuppressive agent for the treatment and prevention of solid organ graft rejection. It is available as an immediate-release, twice-daily formulation (Tacrolimus BID) and a prolonged-release, once-daily formulation (Tacrolimus QD). In a previous study of the pharmacokinetics (PK) of these formulations, mean systemic exposure [area under the curve from 0 to 24 hours (AUC0-24)] of tacrolimus on day 1 was approximately 30% lower for Tacrolimus QD than for Tacrolimus BID; by day 14, systemic exposure was similar; however, the mean dose of Tacrolimus QD was higher to achieve similar systemic exposure as Tacrolimus BID. To further compare the PK of the tacrolimus formulations during the first 2 weeks posttransplant, a substudy was performed in a subset of patients enrolled into a phase III trial in de novo kidney transplant recipients comparing Tacrolimus QD and Tacrolimus BID. To minimize the difference in exposure observed in the earlier study, tacrolimus therapy was initiated before transplant. The PK analysis set comprised 34 patients (17 patients per treatment group) who had 4 complete PK profiles and no major PK-related protocol violations. Mean AUC0-24 of tacrolimus on day 1 was approximately 16% lower for Tacrolimus QD than for Tacrolimus BID, although by day 3 onward, the exposure was similar between treatment groups. Analysis of dose-normalized AUC0-24 (dose normalized to 0.1 mg/kg) showed a similar pattern. There was a good correlation between AUC0-24 and concentration of tacrolimus at 24 hours postdose for both formulations (Tacrolimus QD, r = 0.87; Tacrolimus BID, r = 0.92), and the slope of the line of best fit was similar. These results suggest that initiating tacrolimus therapy before transplant reduces the difference in exposure between Tacrolimus QD and Tacrolimus BID.

Pharmacokinetics in Stable Kidney Transplant Recipients After Conversion From Twice-Daily to Once-daily Tacrolimus Formulations

A prolonged-release formulation of tacrolimus for once-daily administration (Tacrolimus QD) has been developed to offer potential improvements in patient adherence. This study compared the pharmacokinetics (PK) of tacrolimus in stable kidney transplant recipients before and after conversion from twice-daily tacrolimus (Tacrolimus BID) to Tacrolimus QD. This was an open-label, multicenter replicate design study in stable adult kidney transplant recipients (≥6 months posttransplantation) maintained on Tacrolimus BID. Patients underwent four sequential 14-day treatment periods of alternating Tacrolimus BID and QD (mg:mg conversion). Four 24-hour PK profiles were collected, one on the last day of each treatment period. Adverse events were also reported. A total of 60 of 69 patients completed all 4 PK profiles. Steady-state tacrolimus area under the curve from 0 to 24 hours and Cmin were comparable for both formulations, with treatment ratio means (90% confidence intervals) of 92.9% (89.8%-96.0%) and 90.9% (87.3%-94.6%), respectively (acceptance interval: 80%-125%). Both formulations were well tolerated, with renal function remaining stable over the 8-week period. There was a good correlation between area under the curve from 0 to 24 hours and Cmin for Tacrolimus QD and BID (r = 0.88 and 0.82, respectively). The relationship between these two parameters was also similar. The results of this study provide evidence for safe conversion from Tacrolimus BID to QD with appropriate trough concentration monitoring.

Renal function, efficacy and safety postconversion from twice- to once-daily tacrolimus in stable liver recipients: an open-label multicenter study

This multicenter, open-label, phase III study assessed renal function, safety, and efficacy in stable adult liver transplant recipients converted from tacrolimus twice-daily (BID) to once-daily (QD). Patients received tacrolimus BID for 6weeks before conversion to tacrolimus QD (1:1 [mg:mg] total daily dose basis) for 12weeks. Primary endpoint: change in steady state creatinine clearance (CrCl) between treatment phases. Of 112 patients enrolled, 98 were converted to QD dosing (full analysis set [FAS]). Mean (SD) tacrolimus dose was 3.7 (1.7) mg/day during BID and at conversion, and 3.9 (1.8) mg/day at Week 12. 74.5% of patients required no dose adjustment on conversion (FAS). Mean tacrolimus whole blood trough levels were at the lower end of the recommended range during tacrolimus BID and QD; the difference between mean steady-state trough levels was statistically significant (7.5ng/ml vs. 6.5ng/ml; P<0.0001). Following conversion, mean tacrolimus trough levels were reduced by 15% (about 1ng/ml) without any cases of acute rejection, remained stable during the remainder of the study, and were more consistent, showing reduced between- and within-patient variability in trough levels. Renal function remained stable, demonstrating noninferiority of tacrolimus QD versus BID (relative difference in mean calculated CrCl -0.1% [±6.3%]). Patient and graft survival were 100%. Adverse events incidence was low during both treatment phases.

Conversion to tacrolimus once-daily from ciclosporin in stable kidney transplant recipients: a multicenter study

This 24-week, open, single-arm, prospective, multicenter study evaluated the effects of conversion from ciclosporin to Tacrolimus QD in adult kidney transplant patients. Stable patients receiving ciclosporin were converted to Tacrolimus QD at 0.1mg/kg/day. Relative change in renal function (primary endpoint) was assessed using estimated creatinine clearance (eCrCl) with a noninferiority margin set at -10%. A total of 346 patients were enrolled; and 301 patients were treated per protocol (PPS) in the hyperlipidemia (n=42), hypertrichosis (n=106), hypertension (n=77) and gingival hyperplasia (n=76) groups. Relative change in eCrCl was -0.6% in all PPS patients (95% CI, -2.2; 0.9) and -5.3% in the hyperlipidemia (CI, -9.59; -0.97), 0.9% in the hypertrichosis (CI, -2.59; 4.45), -0.1% in the hypertension (CI, -3.8; 3.68), and -1% in the gingival hyperplasia groups (CI, -4.63; 2.65) (PPS), meeting noninferiority criteria. There was no acute rejection. Decreases in serum lipids and blood pressure were moderate but without meaningful change in the number of treatment medications. Substantial decreases in severity of ciclosporin-related cosmetic side effects were evident from investigator and patient self-report of symptoms. Renal function remained stable after conversion to Tacrolimus QD. The effect of conversion on cardiovascular parameters was not clinically meaningful, however, marked improvement in ciclosporin-related cosmetic side effects was observed. (ClinicalTrials.gov number: NCT00481481).

Renal function and safety in stable kidney transplant recipients converted from immediate-release to prolonged-release tacrolimus

This multicenter, open, phase IIIb study assessed short-term efficacy, safety and dose adjustments in adult stable renal transplant recipients converted from tacrolimus twice-daily (BID) to once-daily (QD). Patients receiving unchanged tacrolimus BID for ≥ 12 weeks were enrolled, and after 6-weeks, converted from tacrolimus BID to QD (morning dose) on a 1 : 1 (mg : mg) total daily dose basis, for a further 12 weeks. Primary endpoint: change in steady-state creatinine clearance between treatment phases. Secondary endpoints: biopsy-proven acute rejection (BPAR), patient and graft survival, safety. 128 patients enrolled (mean age 48.9 years; time post-transplant 48.9 months); 91 evaluated for the primary endpoint. Mean total daily dose was 0.06 mg/kg (BID) and 0.07 mg/kg (QD); 79.1% required one/no dose changes post-conversion to maintain recommended blood-trough levels; average dose increase was small (0.6-0.7 mg/day) with more dose increases in patients on the lowest tacrolimus BID doses. Renal function remained stable and non-inferiority of tacrolimus QD against tacrolimus BID was demonstrated. There were no BPAR episodes; patient and graft survival were 100%. Adverse events were few; none led to dose modifications/discontinuation. Tacrolimus BID to tacrolimus QD conversion is straightforward and does not compromise renal function in stable kidney transplant patients in the short term.

Pharmacokinetics in stable heart transplant recipients after conversion from twice-daily to once-daily tacrolimus formulations

A prolonged-release formulation of tacrolimus for once-daily administration (tacrolimus QD) has been developed. This phase II, open-label, multicenter, prospective single-arm study compared the pharmacokinetics (PK) of tacrolimus in stable heart transplant patients before and after conversion from twice-daily tacrolimus (tacrolimus BID) to tacrolimus QD. Heart transplant recipients (≥6 months after transplant), previously maintained on tacrolimus BID-based therapy, received tacrolimus BID from Days 1 to 7 and were converted on a 1:1 (mg/mg) basis to tacrolimus QD. Five 24-hour PK profiles were collected (Days 1, 7, 8, 14, 21). Safety parameters were also evaluated. Of 85 patients, 45 (50.6%) completed all 5 evaluable PK profiles. Steady-state tacrolimus area under the curve, 0 to 24 hours (AUC(0-24)) and minimum concentration (C(min)) were comparable for both formulations, with treatment ratio means of 90.5% (90% confidence intervals [CI], 86.4%-94.6%) and 87.4% (95% CI, 82.9%-92.0%), respectively (acceptance interval, 80%-125%). There was good correlation between AUC(0-24) and C(min) for tacrolimus QD (r = 0.94) and BID (r = 0.91). The relationship between these 2 parameters was also similar. This study provides evidence for successful conversion from tacrolimus BID to QD on a 1:1 (mg/mg) total daily dose basis. Approximately one-third of patients may require dose adjustments. Both formulations were well tolerated, with stable renal function during the study. Adverse events were reported by approximately one-tenth of patients receiving tacrolimus BID and a quarter of those who received QD.

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

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 = 67; bid, n = 62). PK data were available for 77 patients (tacrolimus qd, n = 45; bid, n = 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 ng · h/mL, respectively), but by day 14 was comparable between treatments (324 and 287 ng · h/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 = 0.92 and r = 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 no marked differences in incidence, nature, or severity of adverse events between treatments (although the study was not powered to draw efficacy conclusions). These results suggest that targeting the same trough levels will achieve similar total AUC over 24 hours for both tacrolimus qd and tacrolimus bid in de novo liver transplant recipients.