Twice-daily Tacrolimus Research Articles

Once-daily prolonged-release tacrolimus (Advagraf®) versus twice-daily tacrolimus (Prograf®) in de novo living-donor liver transplantation: a phase IV, randomized, open-label, comparative, single-center study

Once-daily prolonged-release tacrolimus (Advagraf®) versus twice-daily tacrolimus (Prograf®) in de novo living-donor liver transplantation: a phase IV, randomized, open-label, comparative, single-center study

Risk Factors for the Adverse Events after Conversion from Twice-Daily to Once-Daily Tacrolimus in Stable Liver Transplantation Patients.

Despite the therapeutic equivalence between twice-daily and once-daily tacrolimus, patient safety after conversion is still a concern. We reviewed 218 liver transplantation (LT) patients who converted twice-daily to once-daily tacrolimus between May 2011 and January 2014. Thirty (13.8%) patients had adverse events after conversion, with a liver function test (LFT) abnormality being the most common adverse event (n = 17). Despite the decrease in serum tacrolimus of > 30% after conversion, none of the patients who were converted to a dosage ratio (once-daily tacrolimus dosage: twice-daily tacrolimus dosage) > 1 had an LFT abnormality. Most patients with an LFT abnormality improved after increasing the once-daily tacrolimus dosage (n = 2), returned to a previous medication, and/or added another immunosuppressant (n = 15). One patient had acute cellular rejection, which improved after steroid pulse treatment, and another patient had graft failure. In patients with a dosage ratio ≤ 1, the conversion time within 5 years after LT was the only significant risk factor for an LFT abnormality after conversion (odds ratio: 11.850, 95% confidence interval: 1.321–106.325, P = 0.027). In conclusion, the dosage ratio and time after LT should be carefully considered during conversion from twice-daily to once-daily tacrolimus.

Novel Once-Daily Extended-Release Tacrolimus Versus Twice-Daily Tacrolimus in De Novo Kidney Transplant Recipients: Two-Year Results of Phase 3, Double-Blind, Randomized Trial

1-year data from this trial showed the noninferiority of a novel once-daily extended-release tacrolimus (LCPT; Envarsus XR) to immediate-release tacrolimus (IR-Tac) twice daily after kidney transplantation. Final 24-month analysis of a 2-armed, parallel-group, randomized, double-blind, double-dummy, multicenter, phase 3 trial. 543 de novo kidney recipients randomly assigned to LCPT (n=268) or IR-Tac (n=275); 507 (93.4%) completed the 24-month study. LCPT tablets once daily at 0.17 mg/kg/d or IR-Tac twice daily at 0.1 mg/kg/d; subsequent doses were adjusted to maintain target trough ranges (first 30 days, 6-11 ng/mL; thereafter, 4-11 ng/mL). The intervention was 24 months; the study was double blinded for the entirety. Treatment failure (death, transplant failure, biopsy-proven acute rejection, or loss to follow up) within 24 months. Safety end points included adverse events, serious adverse events, new-onset diabetes, kidney function, opportunistic infections, and malignancies. Pharmacokinetic measures included total daily dose (TDD) of study drugs and tacrolimus trough levels. 24-month treatment failure was LCPT, 23.1%; IR-Tac, 27.3% (treatment difference, -4.14% [95% CI, -11.38% to +3.17%], well below the +10% noninferiority criterion defined for the primary 12-month end point). Subgroup analyses showed fewer treatment failures for LCPT versus IR-Tac among black, older, and female recipients. Safety was similar between groups. From month 1, TDD was lower for LCPT; the difference increased over time. At month 24, mean TDD for LCPT was 24% lower than for the IR-Tac group (P<0.001), but troughs were similar (means at 24 months: LCPT, 5.47 ± 0.17 ng/mL; IR-Tac, 5.8 ± 0.30 ng/mL; P=0.4). Trial participant eligibility criteria may limit the generalizability of results to the global population of de novo kidney transplant recipients. Results suggest that once-daily LCPT in de novo kidney transplantation has comparable efficacy and safety profile to that of IR-Tac. Lower TDD reflects LCPT's improved bioavailability and absorption.

Evaluating the economic implications of non-adherence and antibody-mediated rejection in renal transplant recipients: the role of once-daily tacrolimus in the UK

Background and aims:While short-term kidney graft survival has gradually improved over time, improvements in long-term graft survival have been more modest. One key clinical factor limiting improved longer-term outcomes is antibody-mediated rejection (AbMR), the incidence of which appears to be higher in patients who are non-adherent to immunosuppressants. Recent data show that adherence can be improved by reducing pill burden. The aim of the present study was to model the incidence and economic consequences of graft loss and AbMR in patients taking once- vs twice-daily tacrolimus in the UK.Methods:A combined decision tree and Markov model was developed to estimate the incidence of graft failure, AbMR and mortality in renal transplant recipients taking once- vs twice-daily tacrolimus. Underlying rates of graft failure and mortality were derived from UK-specific sources. Proportions of patients adherent to once- vs twice-daily tacrolimus were taken from a recent randomized clinical trial and relative risks of graft failure and AbMR were taken from a prospective, multi-center analysis of 315 patients. Cost data were taken from the British National Formulary and National Health Service reference costs and reported in 2014 pounds sterling.Results:Modeling results showed that improved adherence would be associated with reduced incidence of AbMR and graft failure in renal transplant recipients. Based on improvements in adherence resulting from switching from twice-daily to once-daily tacrolimus, the modeling analysis projected cost savings of GBP 4862 per patient over 5 years with Advagraf relative to Prograf, on absolute costs of GBP 40,974 and GBP 45,836, respectively.Conclusions:Using Advagraf in place of Prograf in renal transplant recipients was predicted to be associated with lower pharmacy, dialysis and AbMR treatment costs, with the reduction in AbMR and dialysis costs being driven by improved adherence to the Advagraf regimen and consequent reductions in graft failure and onset of AbMR.

Medium-Term Renal Function in a Large Cohort of Stable Kidney Transplant Recipients Converted From Twice-Daily to Once-Daily Tacrolimus

BackgroundThere is some evidence pointing toward better renal function in kidney transplant recipients (KTR) treated with once-daily tacrolimus (QD-TAC) vs. twice-daily tacrolimus (BID-TAC).MethodsThis is an extension study of a 1-year, single arm prospective study of stable KTR who were converted from BID-TAC to QD-TAC (4.9 ± 4.0 years after transplantation) in Spanish routine clinical practice. Patient and graft survival, renal function, acute rejection episodes, and other analytic parameters were assessed at 24 and 36 months after conversion.ResultsA total of 1798 KTR were included in the extension study. Tacrolimus doses at 36 months were significantly lower compared to those at time of conversion (−0.2 mg/day; P = 0.023). Blood levels were lower than baseline during all the study (P < 0.001). Graft and patient survival at 3 years after conversion were 93.9% and 95.1%, respectively. Compared with baseline, the mean estimated glomerular filtration rate (eGFR) remained very stable at all timepoints (56.7 ± 19.8 vs 58.1 ± 24.6 mL/min per 1.73 m2 at month 36; P = 0.623). Even when patients reinitiating dialysis were counted as eGFR = 0, the mean eGFR was very stable. In fact, a small but significant increase was observed at 36 months versus baseline (+0.1 mL/min per 1.73 m2; P = 0.025). An increase in proteinuria was observed at 36 months versus baseline (+0.11 g/24 h; P < 0.001). Acute rejection rates were low during the study.ConclusionsConversion from BID-TAC to QD-TAC in a large cohort of stable KTR was safe and associated with a very stable renal function after 3 years. Comparative studies are warranted to assess the feasibility of such conversion.

Conversion of twice-daily to once-daily tacrolimus is safe in stable adult living donor liver transplant recipients

Once-daily extended-release tacrolimus (Tac-OD) has been introduced as a useful therapeutic option to increase patient adherence to immunosuppressive therapy. This study aimed to evaluate the safety, efficacy and immunosuppressant adherence of conversion from twice-daily tacrolimus (Tac-BID) to Tac-OD in stable adult living donor liver transplant (LDLT) recipients in a single institution. Between February and May 2013, Tac-BID was converted to Tac-OD in recipients followed up for at least 12 months after transplantation and without previous rejection episodes. The switching policy was based on a dose ratio of 1:1 with dose adjustment target trough levels at 3-5 ng/mL. Tacrolimus trough levels, laboratory parameters, metabolic disorders, and adverse events were assessed. A total of 229 patients were enrolled in the study. The median age at conversion was 53 years (range 31-73). The median transplant duration was 35.3 months (range 12.0-95.4). During a median follow-up of 13.5 months after conversion, 9 patients returned to Tac-BID because of adverse events. No acute rejection episodes were observed. Of 214 patients still on Tac-OD at 12 months, 12 (5.6%) received a reduced dose and 95 (44.4%) required an increased dose over baseline. Overall adherence was 82.2% at the end of follow-up. The conversion from Tac-BID to Tac-OD with similar target trough levels after conversion is safe and effective for long-term stable LDLT patients.

Clinical Pharmacokinetics of Once-Daily Tacrolimus in Solid-Organ Transplant Patients.

Tacrolimus is a pivotal immunosuppressant agent used in solid-organ transplantation. It was originally formulated for oral administration as Prograf(®), a twice-daily immediate-release capsule. In an attempt to improve patient adherence, retain manufacturer market share and/or reduce health care costs, newer once-daily prolonged-release formulations of tacrolimus (Advagraf(®) and Envarsus(®)XR) and various generic versions of Prograf(®) are becoming available. Tacrolimus has a narrow therapeutic index. Small variations in drug exposure due to formulation differences can have a significant impact on patient outcomes. The aim of this review is to critically analyse the published data on the clinical pharmacokinetics of once-daily tacrolimus in solid-organ transplant patients. Forty-three traditional (non-compartmental) and five population pharmacokinetic studies were identified and evaluated. On the basis of the stricter criteria for narrow-therapeutic-index drugs, Prograf(®), Advagraf(®) and Envarsus(®)XR are not bioequivalent [in terms of the area under the concentration-time curve from 0 to 24h (AUC0-24) or the minimum concentration (C min)]. Patients may require a daily dosage increase if converted from Prograf(®) to Advagraf(®), while a daily dosage reduction appears necessary for conversion from Prograf(®) to Envarsus(®)XR. Prograf(®) itself, or generic immediate-release tacrolimus, can be administered in a once-daily regimen with a lower than double daily dose being reported to give 24-h exposure equivalent to that of a twice-daily regimen. Intense clinical and concentration monitoring is prudent in the first few months after any conversion to once-daily tacrolimus dosing; however, there is no guarantee that therapeutic drug monitoring strategies applicable to one formulation (or twice-daily dosing) will be equally applicable to another. The correlation between the tacrolimus AUC0-24 and C min is variable and not strong for all three formulations, indicating that trough measurements may not always give a good indication of overall drug exposure. Further investigation is required into whether the prolonged-release formulations have reduced within-subject pharmacokinetic variability, which would be a distinct advantage. Whether the effects of factors that influence tacrolimus absorption and pre-systemic metabolism (patient genotype status; gastrointestinal disease and disorders) and drug interactions differ across the formulations needs to be further elucidated. Most pharmacokinetic comparison studies to date have involved relatively stable patients, and many have been sponsored by the pharmaceutical companies manufacturing the new formulations. Larger randomized, controlled trials are needed in different transplant populations to determine whether there are differences in efficacy and toxicity across the formulations and whether formulation conversion is worthwhile in the longer term. While it has been suggested that once-daily administration of tacrolimus may improve patient compliance, further studies are required to demonstrate this. Mistakenly interchanging different tacrolimus formulations can lead to serious patient harm. Once-daily tacrolimus is now available as an alternative to twice-daily tacrolimus and can be used denovo in solid-organ transplant recipients or as a different formulation for existing patients, with appropriate dosage modifications. Clinicians need to be fully aware of pharmacokinetic and possible outcome differences across the different formulations of tacrolimus.

Impact of Conversion From Advagraf to Twice-Daily Generic Tacrolimus in Kidney Transplant Recipients: A Single-Center Study

BackgroundThe conversion of twice-daily (Prograf) to once-daily tacrolimus (Advagraf) as well as from Prograf to a generic tacrolimus preparation was proved to be safe in kidney transplant patients. There are no published studies comparing the clinical outcomes of patients who were receiving Advagraf and were switched to generic preparations of tacrolimus. ObjectivesTo evaluate the impact, safety profile, side effects, and renal graft function after the conversion of Advagraf to a generic preparation of tacrolimus. Population and MethodsThis prospective study was conducted over a 9-month period. The conversion to twice-daily generic tacrolimus was performed on a 1 mg:1 mg basis, total daily dose. We included 123 kidney transplant recipients (55% male). The mean (± SD) age was 49.9 ± 12 years. There were 100 (81%) Caucasian patients; the mean (± SD) time from transplantation to conversion was 4.6 ± 4.4 years. ResultsA significant increase in blood levels (18%; P = .000) was reported. There was a necessary tacrolimus dose reduction of 17% (P = .000) and ≥3 blood trough levels to adjust the initial tacrolimus blood levels. The mean serum creatinine remained stable before conversion, at months 1 and 6 (1.40, 1.43, and 1.46 mg/dL, respectively). Significant adverse effects were reported in 9% of our patients. There were no episodes of acute rejection or graft loss during the study. ConclusionsThe conversion proved to be safe. A drug reduction was necessary to ensure stable renal function and good tolerability.

Novel Once-Daily Extended-Release Tacrolimus (LCPT) Versus Twice-Daily Tacrolimus in De Novo Kidney Transplants: One-Year Results of Phase III, Double-Blind, Randomized Trial

This Phase III randomized trial examined efficacy and safety of a novel once-daily extended-release tacrolimus formulation (LCP-Tacro [LCPT]) versus twice-daily tacrolimus in de novo kidney transplantation. Primary efficacy end point was proportion of patients with treatment failure (death, graft failure, biopsy-proven acute rejection or lost to follow-up) within 12 months. Starting doses were, LCPT: 0.17 mg/kg/day and tacrolimus twice-daily: 0.1 mg/kg/day; 543 patients were randomized, LCPT: n = 268; tacrolimus twice-daily: n = 275. At 12 months treatment failure was LCPT: 18.3% and tacrolimus twice-daily: 19.6%; the upper 95% CI of the treatment difference was +5.27%, below the predefined +10% noninferiority criteria. There were no significant differences in the incidence of individual efficacy events or adverse events. Target tacrolimus trough levels were more rapidly achieved in the LCPT group. Following initial dose, 36.6% of patients in the LCPT group had rapidly attained trough levels within 6-11 ng/mL versus 18.5% of tacrolimus twice-daily patients; majority of tacrolimus twice-daily patients (74.7%) had troughs <6 ng/mL compared with 33.5% in the LCPT group. Overall, cumulative study dose was 14% lower for LCPT. Results suggest that use of once-daily LCPT in de novo kidney transplantation is efficacious and safe. Lower LCPT dose reflects the improved absorption provided by the novel formulation.

Extended-release tacrolimus: a review of its use in de novo kidney transplantation.

Extended-release tacrolimus (tacrolimus ER) [Advagraf(®); Astagraf XL(®); Graceptor(®); Prograf XL(®)] is a once-daily formulation of the immunosuppressive calcineurin inhibitor, which is approved in many countries worldwide for the prophylaxis of transplant rejection in adult de novo kidney transplant recipients. It is absorbed more slowly than the conventional, twice-daily, immediate-release formulation, initially producing lower exposure when administered at the same daily dosage, but providing equivalent exposure upon repeat administration with therapeutic drug monitoring. In randomized, controlled, phase III/IV trials, with extended follow-up to 4years, the efficacy of tacrolimus ER was similar to that of twice-daily tacrolimus with regard to the prevention of acute rejection or graft dysfunction in adult de novo kidney transplant recipients. Renal function was significantly better with tacrolimus ER, but not tacrolimus, than with ciclosporin. The tolerability profile of tacrolimus ER was descriptively similar to that of the original twice-daily formulation, with no notable differences. Therefore, tacrolimus ER retains the immunosuppressive activity of the original formulation in the prophylaxis of transplant rejection in adult de novo kidney transplant recipients and offers the benefits of once-daily administration.

Update on the clinical utility of once-daily tacrolimus in the management of transplantation.

Adherence to immunosuppression and minimizing variability in drug exposure are important considerations in preventing rejection and maximizing overall transplant outcomes. The availability of once-daily tacrolimus may confer potential benefit by simplifying immunosuppressive regimens, thereby improving medication adherence among transplant recipients. Pharmacokinetic studies in healthy normal volunteers and stable transplant recipients suggest that once-daily tacrolimus is bioequivalent to twice-daily tacrolimus. Efficacy studies suggest that once-daily tacrolimus is noninferior to twice-daily tacrolimus with a concentration-dependent rejection risk. The incidence of biopsy-proven acute rejection, graft survival, and patient survival are more or less comparable between the two tacrolimus formulations. Once-daily tacrolimus has also been reported to have favorable effects on blood pressure, lipid profile, and glucose tolerance. Once-daily tacrolimus may be a viable option to consider for de novo immunosuppression or for conversion from conventional tacrolimus.

Pharmacokinetic and CYP3A5 pharmacogenetic differences between once- and twice-daily tacrolimus from the first dosing day to 1 year after renal transplantation.

Aim & patients & methods: This study investigated 24-h pharmacokinetic and CYP3A5 pharmacogenetic differences between once-daily tacrolimus (Tac-q.d.) versus twice-daily tacrolimus (Tac-b.i.d.) pretransplantation and at 1 month and 1 year post-transplantaion. The dose-adjusted trough level (Cmin) and area under the blood concentration-time curve from 0 to 24 h (AUC₀₋₂₄) increased twofold within 1 year post-transplantation with both formulations and the two genotypes. Good correlations were observed between the AUC₀₋₂₄ and Cmin for both formulations. However, the dose-adjusted Cmin, but not dose-adjusted AUC₀₋₂₄, was approximately 30% lower for Tac-q.d. than for Tac-b.i.d. Although the dose-adjusted Cmin was lower for Tac-q.d. than for Tac-b.i.d. in both genotypes, the dose-adjusted AUC₀₋₂₄ was approximately 25% lower for Tac-q.d. than for Tac-b.i.d. in CYP3A5 expressers, but not in nonexpressers during the study period. These results suggested that the approximately 30% lower Cmin for Tac-q.d. than for Tac-b.i.d. may have achieved the same AUC₀₋₂₄ with both formulations and may be associated with CYP3A5 pharmacogenomic differences, especially in CYP3A5 expressers, between Tac-b.i.d. and Tac-q.d.

Comparison of Once-Daily and Twice-Daily Low-Dose Tacrolimus in Living Related Kidney Transplantation -Prospective Trial of Once-Daily vs. Twice-Daily Tac -3 Years Second Report.

Background; A prolonged-release formulation of Tacrolimus (Tac-QD) has been developed to allow once-daily dosing with a similar safety and efficacy profile to that of twice-daily tacrolimus (Tac-BD). Previously, we reported a comparison of the safety and pharmacokinetics between Tac-QD and BD in the early phase after kidney transplantation. In this study, we report longer-term results in the same recipient population 3 years after the aforementioned prospective study. Materials and methods; Between November 2009 and January 2011, 130 consecutive adult patients were randomized to receive either low-dose Tac-QD or Tac-BD. The transplant operation was cancelled due to other reasons after enrollment in this study in 9 cases. During the 3- to 5-years' observation period, the treatment was switched from Tac-BD to Tac-QD in 5 cases, and from Tac-QD to Tac-BD in 2 cases. The drug itself was switched from tacrolimus to cyclosporine in 2 cases. One patient died and 5 cases lost their grafts. In the remaining 106 cases included as the subjects of this study, we examined the patient and graft survival rates, the incidence rates of graft rejection, the serum tacrolimus trough level, and the total oral dose of tacrolimus. Results; The patient survival rates are 100% and 98% in the QD and BD groups. The graft survival rate is 98% in both groups. The current tacrolimus dose is 2.9±1.7 mg/day in the QD group and 2.4±1.2 mg/day in the BD group (P=0.32). The mean tacrolimus trough level is 5.1±0.9 ng/ml in the QD group and 5.0±1.1 ng/ml in the BD group (P=0.81). There is no statistically significant difference in the graft function between the QD and BD groups (serum creatinine level; 1.2±0.4 mg/dl in the QD group vs. 1.1±0.2 mg/dl in the BD group; P=0.55). The incidence rate of acute/chronic T cell-mediated rejection until 3 years after Tx was 10% (2/19) in the QD group and 12 % (3/25) in the BD group (P=0.95). The incidence rate of acute/chronic antibody-mediated rejection until 3 years after Tx was 5% (1/19) in the QD group and 8% (2/25) in the BD group (P=0.87). There has been no significant difference in the graft rejection rate, CNI toxicity, incidence of BK nephropathy and recurrence of IgA nephropathy between the two groups. Conclusion; The clinical efficacy and safety profile of Tac-QD and Tac-BD are almost the same, even 3 to 5 years after kidney transplantation.

Higher Initial Exposure of Envarsus Immediately Post Transplantation Is Not Associated With Increased Risk of Delayed Graft Function in Kidney Transplant Patients Treated With Novel Once-Daily MeltDose Tacrolimus (Envarsus) Vs. Twice-Daily Tacrolimus (Prograf): Results From a Phase 3, Double-Blind, Double-Dummy, Multi-Center, Randomized Trial.

Higher Initial Exposure of Envarsus Immediately Post Transplantation Is Not Associated With Increased Risk of Delayed Graft Function in Kidney Transplant Patients Treated With Novel Once-Daily MeltDose Tacrolimus (Envarsus) Vs. Twice-Daily Tacrolimus (Prograf): Results From a Phase 3, Double-Blind, Double-Dummy, Multi-Center, Randomized Trial.

De Novo Prograf Versus De Novo Advagraf: Are Trough Level Profile Curves Similar?

BackgroundAccording to the clinical trials, Advagraf (ADV) has efficacy and safety profile similar to Prograf (PROG). The aim of this study was to compare the graft functions, dosages, and tacrolimus (TAC) trough level profile curves of patients on de novo PROG and ADV therapy. MethodsThe ADV group included 39 de novo renal cases who had received initial immunosuppression (IS) with once-daily TAC (1 × 0.2 mg/kg from day1 after transplantation). We compared them with a PROG group of 38 transplant patients who received equivalent IS with twice-daily TAC (2 × 0.1 mg/kg from day1). In both groups, the IS was combined with antimetabolites and steroids. The mean follow-up time was similar (13.5 ± 7 days) in both groups after renal transplantation until the emission of the patients from our clinic. ResultsTAC mean total daily dose was reduced and whole-blood trough levels decreased over the time in early postoperative days. Only on day 3 and day 4 after transplant, a significant higher adjustment in the ADV dosage was necessary to achieve sufficient TAC trough levels. The average TAC trough level profile curves were similar in PROG and ADV groups, but the individual curves were very different. Mainly in patients on ADV therapy, the initial concentrations were often >30 ng/mL, and in some cases on the 9th posttransplant day decreased to <5 ng/mL, then slowly increased into the required therapeutic range. ConclusionsThe results demonstrate that patients after renal transplantation can be safely treated de novo with ADV. Setting the required therapeutic TAC blood levels may require more attention to avoid the “fluctuations” of trough level profile curve during the early postoperative period. Our data suggest that dose adjustment of ADV can be carried out more carefully compared with PROG on the basis of clinical symptoms and the value of TAC blood levels to avoid acute rejection and toxicity.

Two-Year Results of Envarsus (Once-Daily MeltDose Tacrolimus Tablets) vs Prograf (Twice-Daily Tacrolimus Capsules): A Phase 3, Double-Blind, Double-Dummy, Multi-Center, Prospective, Randomized Study.

In this Phase 3, double-blind, double-dummy, multi-center, prospective, randomized study, 543 kidney transplant recipients (KTR) (Mean age 56 yrs; 65% male; 77% White, 5% Black; 51% deceased donor) were randomly assigned to Envarsus (N=268 patients [pts]) or Prograf (N=275). 517 pts (95%) completed 1 year followup; to date, 83% of patients (451) have completed the 2 year visit. For the entire two year study only 12 (2%) pts were lost to followup; only 3 pts between year 1 and 2. One year results showed noninferiority to Prograf based on the composite treatment failure primary endpoint (Envarsus 18%, Prograf 20%). Three month failure rates were 10% and 14% respectively. One year analyses of adverse events showed no statistically significant differences. Envarsus patients attained targeted troughs within 1 day of first dose; Prograf levels were achieved within 4 to 7 days. From month 3 onward, Envarsus KTR required a lower daily dose vs. Prograf KTR with similar trough levels, suggesting Envarsus' improved bioavailability. Two year data on estimated glomerular filtration rate of Envarsus and Prograf pts show a steady improvement in renal function over the two year study. Database lock will be in March 2014 and full two year efficacy and safety data on all unblinded pts will be available April 2014. Patient retention was excellent in this large, well-controlled, 2 year trial. Data to date show excellent efficacy and safety with both tacrolimus formulations and a gradual improvement in renal function over the course of two years. Pending the imminent completion of the study, the full two-year followup efficacy and safety results will be available for presentation.Figure: No Caption available.DISCLOSURES:Rostaing, L.: Other, Chiesi, Advisory Board. Bunnapradist, S.: Grant/Research Support, Veloxis, Genentech, Novartis, Speaker's Bureau, Novartis, Other, Veloxis, Advisory Board. Budde, K.: Grant/Research Support, AiCuris, Astellas, BmT GmbH, Bristol-Myers Squibb, speaker's fees, honoraria, travel expenses, Chiesi, Hexal, Novartis, Roche, Pfizer, Siemens, speaker's fees, honoraria, travel expenses, Veloxis, speaker's fees, honoraria, travel expenses, Other, Bristol-Myers Squibb,, Consultant, Chiesi, Effimune, Hexal, Veloxis, Novartis, Consultant.

Intrapatient Variability in Trough Drug Concentrations in Renal Transplant Patients Receiving Branded (Prograf®) and Generic (Adoport®) Tacrolimus: A Retrospective Cohort Analysis.

Introduction Tacrolimus has a narrow therapeutic index; subtherapeutic blood concentrations are associated with inadequate immunosuppression, while acutely high calcineurin inhibitor concentrations may cause nephrotoxicity. High intrapatient variability in trough tacrolimus blood concentrations in the period 6-12 months post-renal transplant is associated with a higher risk of graft failure(Borra,et al. Nephrol Dial Trans 2010;25:2757). The initiator brand of twice-daily tacrolimus (Prograf®) came off-patent in April 2008. Many centres have since moved to a generic formulation (such as Adoport®), leading to considerable interest in comparing pharmacokinetic and clinical profiles of generics with Prograf®. Currently there are no published data on intrapatient variability for patients receiving generic tacrolimus preparations. Methods Our centre switched from Prograf® (initiator) to Adoport® (generic) for de novo renal transplant patients on 1 July 2012. We performed a retrospective cohort study to examine the degree of intrapatient variability in tacrolimus concentration at 6-12 months post-transplant, in patients started on Prograf® and an equivalent cohort started on Adoport® at induction. Trough tacrolimus concentrations measured by immunoassay in outpatient clinics in the 6-12 month period were retrospectively reviewed and adjusted for dose. Intrapatient variability was calculated as coefficient of variation. Results In our preliminary findings from 52 patients (27 on Prograf® and 25 on Adoport®), there was no significant difference in intrapatient variability according to tacrolimus formulation (coefficients of variation 29.9%±14.6 vs 31.4%±16.1, p=0.71). This sample size would detect a net difference in coefficient of variation of 12% with 80% power. This is less than the difference in mean coefficient of variation between the high- and low-variability groups in Borra et al (14.6%), suggesting that we would be likely to detect any clinically significant difference. There was no statistically significant difference between the number of dose changes with Prograf® and Adoport® (0.57±0.78 vs 1.0±0.95 per 100 days of follow-up, p=0.057) but this requires more investigation with a larger sample size. Conclusion Preliminary analysis has found no difference in intrapatient variability of trough tacrolimus concentrations between renal transplant patients taking Prograf® and Adoport®. DISCLOSURES:Popoola, J.: Grant/Research Support, Astellas (manufacturer of Prograf), Financial support of research and conferences, Sandoz (manufacturer of Adoport), Financial support of research and conferences. MacPhee, I.: Grant/Research Support, Astellas (manufacturer of Prograf), Speaker's Bureau, Astellas (manufacturer of Prograf), Speaker honaria;, conference expenses.

Conversion from twice-daily to once-daily extended-release tacrolimus in renal transplant recipients: 2-year results and review of the literature.

Tacrolimus extended-release formulation has been approved for use in Canada since October 2008. In initial studies, efficacy and safety profile were demonstrated as similar for both formulations (twice-daily tacrolimus and extended-release formula tacrolimus). To validate the safety and efficacy of extended-release formula tacrolimus, we conducted a prospective observational study. At our institution, between January 2009 and January 2010, the switch from tacrolimus to extended-release formula tacrolimus was done in 130 stable kidney recipients. Clinical data were accessed at baseline (data before conversion), 1 to 2 weeks, 1 month, 3 months, 6 months, 12 months, and 24 months after conversion. One hundred thirty renal transplant recipients were included in the current study. During the observation period, we saw no acute rejection and no change in graft function (mean serum creatinine levels remained stable). However, compared with baseline, mean tacrolimus trough levels were significantly reduced at 1 to 2 weeks, at 1 month, 6 months, 12 months, and at 24 months after conversion. Regarding the safety profile, no significant changes were noted in blood glucose, potassium, and magnesium. Approximately 35% of recipients preferred the extended-release formula tacrolimus to twice-daily tacrolimus. Conversion from twice-daily tacrolimus to extended-release once-daily tacrolimus appears to be safe and convenient up to 2 years after conversion in some recipients.

Lower Variability in 24-Hour Exposure During Once-Daily Compared to Twice-Daily Tacrolimus Formulation in Kidney Transplantation

Tacrolimus has originally been registered as a twice-daily formulation (Prograf, Tac BID), although a once-daily formulation (Advagraf, Tac QD) is also available. A reduced intrapatient variability of Tac Cmin, a surrogate marker for 24-hour drug exposure (AUC0-24), has been suggested. The variability of AUC0-24 has never been studied prospectively yet. The purpose of this study was to investigate the change in intrapatient variability of Tac AUC0-24 after converting from Tac BID to Tac QD. Forty renal transplant patients on Tac BID were converted on a 1:1 (mg/mg) basis to Tac QD in an investigator-driven comparative pharmacokinetic (PK) study. AUC0-24 was determined five times before and after conversion. Duplicate samples were collected by the patients themselves using the dried blood spot method. The main outcome measure is the change in intrapatient variability of AUC0-24 expressed as coefficient of variation (CV). Moreover, the influence of Cyp3A5 genotype polymorphism on the change in CV was studied. In total, 400 AUC0-24 profiles were available for analysis. Conversion to Tac QD resulted in a significant improvement in intra-patient CV from 14.1% to 10.9% (P=0.012). Patients with the Cyp3A5*1/*3 genotype (n=11) had a numerically larger improvement in CV than patients with the CYP3A5*3/*3 genotype. Intrapatient CV of Tac AUC0-24 improved after converting from Tac BID to Tac QD in stable renal transplant patients, especially in patients with the CYP3A5*1/3 genotype. Given the very strict protocol of this PK study, this improvement is most likely due to the different intrinsic PK properties of Tac QD and Tac BID.

Safety and Efficacy of Once-Daily Modified-Release Tacrolimus in Liver Transplant Recipients: A Multicenter Postmarketing Surveillance in Japan

IntroductionModified-release formulation of tacrolimus (TAC-MR) has been developed with the intent of improving patient adherence and quality of life. A number of studies have indicated that the efficacy and safety of once-daily TAC-MR were comparable with those of the original formulation, twice-daily tacrolimus. However, its dosage, trough level, safety, and efficacy in the multicenter clinical experience of Japanese liver transplant recipients have not been reported. MethodsThis postmarketing surveillance designed as an open-label, prospective, noninterventional observational study was performed. The 24 patients were enrolled for de novo transplantation, and the 122 patients were enrolled for conversion to TAC-MR from 22 medical institutions in Japan. The observation period is 1 year in de novo transplantation, and 24 weeks in conversion. ResultsRegarding de novo transplant, the median daily TAC-MR dose was 0.041 mg/kg/d at 1 day after transplantation, and the median tacrolimus trough level was 5.5 ng/mL at 3 days after transplantation. The most common adverse drug reactions were infections, at an incidence rate of 25.0%. The most common infections were cytomegalovirus viremia, at an incidence rate of 12.5%. Both patient and graft survival rates at 1 year were 94.1% and the rejection rate was 20.8%. Regarding conversion to TAC-MR, the median daily conventional TAC dose before conversion was 1.8 mg/d, and the daily TAC-MR dose was 1.5 mg/d. The median TAC trough level was 3.6 ng/mL before conversion and 3.5 ng/mL 1 week after conversion. The most common adverse drug reactions were infections, at an incidence rate of 5.1%. Episodes of death or graft loss did not occur, and there were 3 episodes of rejection. After conversion to once-daily TAC-MR, the patients' adherence was improved. ConclusionThis study shows that a TAC-MR–based immunosuppressive regimen is safe and effective as used in Japanese clinical practice.