Immediate-release Tacrolimus Research Articles

Advagraf® with or without an induction therapy for de novo kidney-transplant recipients

ABSTRACTIntroduction: Cornerstone immunosuppressive therapy currently relies on immediate-release tacrolimus, a calcineurin inhibitor (CNI) that is potentially nephrotoxic and is more diabetogenic than cyclosporine A. Two new formulations of tacrolimus have been launched: an extended-release formulation (Advagraf®/Astagraf XL®, Astellas company) and a long-lasting formulation (Envarsus®, Veloxis company).Area covered: Herein, we assess the efficacy of an extended-release formulation of tacrolimus (Advagraf®/Astagraf XL®) used in conjunction with or without an induction therapy (i.e., basiliximab) in de novo kidney-transplant recipients. To achieve this, we searched for suitable articles through PubMed.Expert commentary: Phases-III and -IV studies comparing Advagraf®/Astagraf XL® to Prograf® in association with mycophenolate mofetil (more than 2,500 patients) have demonstrated overall similar results with regards to patient/graft survival, biopsy-proven acute-rejection rate, and renal function (p > 0.05). A randomized controlled study in maintenance kidney transplant patients has shown (using electronic monitoring) that, as compared to Prograf®, Advagraf® significantly improved adherence to medication. Other studies report that Advagraf®-treated patients receiving a mTOR-inhibitor agent (sirolimus or everolimus) instead of MMF: this was associated with good allograft outcome, and might also prevent late-onset cytomegalovirus infection. Advagraf®-based immunosuppression given to de novo kidney-transplant recipients, with or without an induction therapy, provided excellent results compared to Prograf®; it also increased patients’ adherence to treatment.

Tacrolimus - Pharmacokinetic Considerations for Clinicians.

The calcineurin inhibitor tacrolimus (Tac) is an integral part of the standard immunosuppressive regimen after renal transplantation (RTx). However, clinical management of Tac therapy can be challenging because of its narrow therapeutic window and because many factors interfere with its metabolism. Therefore, therapeutic drug monitoring is used to adjust the dosage. Recently, we were able to classify patients receiving tacrolimus into two major metabolism groups by simple calculation of the C/D ratio (expressed as the blood concentration normalized by the dose). We showed that the C/D ratio is significantly associated with the (renal) outcome of recipients after kidney and liver transplantation. These findings are interesting and relevant to transplant physicians and physicians interested in immunosuppressive therapy. We therefore review current state of the art aspects of tacrolimus pharmacokinetics including genetics or different tacrolimus formulations (twice-daily immediate-release tacrolimus capsules, once-daily extended- release tacrolimus capsules; novel once-daily tacrolimus tablets) and their possible clinical impact including practical considerations for clinicians.

Sustained-Release Tacrolimus Stabilizes Decline of Forced Expiratory Volume in 1 Second Through Decreasing Fluctuation of Its Trough Blood Level

BackgroundCalcineurin inhibitors are a commonly used immunosuppressive drug and over 80% of lung transplant (LTx) recipients use tacrolimus. Sustained-release tacrolimus (SRT) was developed as a once-daily formulation, resulting in slower release and reduction in peak concentration compared with twice-daily immediate-release tacrolimus (IRT). Previous reports indicate that SRT may carry fewer side effects than IRT; however, the impact of SRT in bronchiolitis obliterans syndrome (BOS) after LTx is unclear. ObjectiveOur study objective was to evaluate the effect of SRT in BOS after LTx. Materials and methodsWe investigated the effect of SRT for BOS among 75 LTx recipients who were alive in 2017 in our LTx program. All analyses were carried out using student t test or F test. ResultsThirty-five recipients took IRT, 32 recipients used SRT, 7 recipients used cyclosporine, and 1 patient who received bone marrow and a lung graft from the same donor did not use a calcineurin inhibitor. The most frequent reason for conversion of IRT to SRT was kidney dysfunction, followed by other IRT complications. Five recipients underwent conversion of IRT to SRT because of decline of forced expiratory volume in 1 second (FEV1) with fluctuation of the tacrolimus trough level. After induction of SRT, the fluctuation of the tacrolimus trough level was significantly reduced in 4 of 5 patients (P < .05). Before drug form conversion, the FEV1 in these 5 patients was significantly decreased; however, this exacerbation of FEV1 was attenuated after SRT induction (P < .05). ConclusionSRT appeared to stabilize decline of FEV1 in patients with BOS possibly due to reducing the fluctuation of tacrolimus trough blood concentration.

Immunosuppression Adherence in Stable Kidney Transplant Patients Converted From Immediate- to Prolonged-Release Tacrolimus in Clinical Practice: A Norwegian Study.

BackgroundThis study investigated medication adherence in kidney transplant patients (KTPs) converted from immediate-release tacrolimus (IR-T) to prolonged-release tacrolimus (PR-T)-based immunosuppression in routine practice.MethodsNoninterventional, observational, multicenter study in Norway. Included adult KTPs with stable graft function, converted from IR-T (baseline) to PR-T (1 mg:1 mg) in routine practice. Data were collected at baseline, and months 1, 3, 6, and 12 postconversion. Primary endpoint: adherence using the Basel Assessment of Adherence to Immunosuppressive Medication Scale. Secondary assessments: tacrolimus dose and trough levels (target, 3-7 ng/mL), clinical laboratory parameters (eg, estimated glomerular filtration rate [Modified Diet in Renal Disease]), and adverse events.ResultsNinety-one KTPs (mean ± SD age 47.7 ± 14.3 years) were analyzed. Mean ± SD change in PR-T dose from baseline (4.4 ± 2.4 mg/d) to month 12 was −0.1 ± 0.9 mg/d; mean tacrolimus trough levels remained within target. Overall medication adherence increased from 45.6% at baseline to 58.1% at month 1, but was similar to baseline thereafter; taking and timing adherence followed a similar pattern. Odds ratio (OR) for adherence at month 1 (but not at other time points) was greater versus baseline for overall (OR, 1.71; P = 0.0205), taking (OR, 3.38; P = 0.0004), and timing (OR, 1.77, P = 0.0252) dimensions. Mean ± SD Basel Assessment of Adherence to Immunosuppressive Medication Scale visual analogue scale score at baseline was 96.4 ± 5.5%, and increased postconversion. Estimated glomerular filtration rate remained stable (month 12, 61.6 ± 17.7 mL/min per 1.73 m2), as did other laboratory parameters. Two (2.2%) patients had adverse events considered probably/possibly treatment-related.ConclusionsThere was disparity between high, patient-perceived and low, actual adherence. Converting stable KTPs from IR-T to PR-T in routine practice did not impact long-term adherence to immunosuppression; renal function remained stable.

Evaluation of adherence and tolerability of prolonged-release tacrolimus (Advagraf™) in kidney transplant patients in Germany: A multicenter, noninterventional study.

This study assessed adherence to prolonged-release tacrolimus (PR-T)-based immunosuppression during routine maintenance of renal transplant recipients in Germany. Patients had received PR-T for ≥1month at inclusion. Data were collected during four visits (V): baseline (V1), 6 (V2), 12 (V3), and 18 (V4) months. Composite primary endpoint: nonadherence at V4, defined as self-reported nonadherence on the Basel Assessment of Adherence with Immunosuppressive Medication Scale (BAASIS© ), investigator-rated nonadherence, and/or V4 tacrolimus trough level outside a predefined range. Secondary endpoints: individual BAASIS items, incidence of rejection, kidney function, and safety. Overall, 153 adult kidney recipients (mean [standard deviation] time post-transplant 5.8 [4.6]years) were included. Nonadherence was high at V4 (67.7% [95% confidence interval 58.9%, 75.6%]). Medication-taking adherence was 86.9% and 91.3% at V1 and V4, respectively; adherence to timing of medication intake was 58.2% and 58.3%, with little evidence of missed doses/drug holidays. Investigators rated adherence "good" in 85.6% of patients (V4). Two (1.3%) patients had acute rejection episodes. Kidney function remained stable (mean creatinine clearance, V1: 62.1mL/min; V4: 65.3mL/min). Investigators rated effectiveness of PR-T as "very good"/"good" in 91.5% of patients. Most patients (94.7%) found PR-T dosing more convenient than immediate-release tacrolimus. PR-T was well tolerated with high medication persistence.

Results of ASERTAA, a Randomized Prospective Crossover Pharmacogenetic Study of Immediate-Release Versus Extended-Release Tacrolimus in African American Kidney Transplant Recipients

Differences in tacrolimus dosing across ancestries is partly attributable to polymorphisms in CYP3A5 genes that encode tacrolimus-metabolizing cytochrome P450 3A5 enzymes. The CYP3A5*1 allele, preponderant in African Americans, is associated with rapid metabolism, subtherapeutic concentrations, and higher dose requirements for tacrolimus, all contributing to worse outcomes. Little is known about the relationship between CYP3A5 genotype and the tacrolimus pharmacokinetic area under the curve (AUC) profile in African Americans or whether pharmacogenetic differences exist between conventional twice-daily, rapidly absorbed, immediate-release tacrolimus (IR-Tac) and once-daily extended-release tacrolimus (LifeCycle Pharma Tac [LCPT]) with a delayed absorption profile. Randomized prospective crossover study. 50 African American maintenance kidney recipients on stable IR-Tac dosing. Recipients were randomly assigned to continue IR-Tac on days 1 to 7 and then switch to LCPT on day 8 or receive LCPT on days 1 to 7 and then switch to IR-Tac on day 8. The LCPT dose was 85% of the IR-Tac total daily dose. Tacrolimus 24-hour AUC (AUC0-24), peak and trough concentrations (Cmax and Cmin), time to peak concentration, and bioavailability of LCPT versus IR-Tac, according to CYP3A5 genotype. CYP3A5 genotype, 24-hour tacrolimus pharmacokinetic profiles. ∼80% of participants carried the CYP3A5*1 allele (CYP3A5 expressers). There were no significant differences in AUC0-24 or Cmin between CYP3A5 expressers and nonexpressers during administration of either IR-Tac or LCPT. With IR-Tac, tacrolimus Cmax was 33% higher in CYP3A5 expressers compared with nonexpressers (P=0.04): With LCPT, this difference was 11% (P=0.4). This was primarily a pharmacogenetic study rather than an efficacy study; the follow-up period was too short to capture clinical outcomes. Achieving therapeutic tacrolimus trough concentrations with IR-Tac in most African Americans results in significantly higher peak concentrations, potentially magnifying the risk for toxicity and adverse outcomes. This pharmacogenetic effect is attenuated by delayed tacrolimus absorption with LCPT. Registered at ClinicalTrials.gov, with study number NCT01962922.

Efficacy of Prolonged- and Immediate-release Tacrolimus in Kidney Transplantation: A Pooled Analysis of Two Large, Randomized, Controlled Trials

BackgroundTwo large, prospective studies (12-03; OSAKA) compared the efficacy and tolerability of prolonged-release versus immediate-release tacrolimus in kidney transplant patients also receiving mycophenolate mofetil and low-dose corticosteroids (without induction therapy). MethodsData were combined into one database to compare results over 24 weeks using 3 alternative endpoints: biopsy-confirmed acute rejection (BCAR); the Food and Drug Administration composite endpoint (graft loss, BCAR, and loss to follow-up), and the European Medicines Agency composite endpoint (graft loss, BCAR, and graft dysfunction). The 95% confidence intervals were calculated (10% noninferiority margin). ResultsOverall, 633 patients received prolonged-release tacrolimus (12-03, n = 331; OSAKA, n = 302) and 645 received immediate-release tacrolimus (n = 336; n = 309). Baseline characteristics were comparable. Proportionately more patients receiving prolonged-release tacrolimus had trough levels of 5–15 ng/mL on day 1 (60.8%) and 2 (56.6%) versus immediate-release tacrolimus (42.5% and 43.9%, respectively, both P < .001). Efficacy of prolonged-release and immediate-release tacrolimus were similar as assessed by BCAR (13.9% vs 14.1%, respectively), European Medicines Agency composite endpoint (40.3% vs 38.3%) and US Food and Drug Administration composite endpoint (21.5% vs 19.8%). ConclusionsNovel efficacy endpoints as required by the European Medicines Agency and US Food and Drug Administration demonstrate noninferiority of prolonged-release versus immediate-release tacrolimus. Significantly more patients treated with prolonged-release tacrolimus versus immediate-release tacrolimus achieved trough levels of 5 to 15 ng/mL early after transplantation. ClinicalTrials.govNCT00189839; NCT00717470.

Development of extended-release solid dispersion granules of tacrolimus: evaluation of release mechanism and human oral bioavailability

We aimed to prepare a once-daily modified-release oral formulation of tacrolimus by utilizing an extended-release granules (ERG). Extended-release granules were prepared using ethylcellulose (EC), hydroxypropylmethylcellulose (HPMC) and lactose via a solvent evaporation method with ethanol. Physicochemical and biopharmaceutical studies were performed to determine the formulation with optimum release profile of tacrolimus from ERG. Tacrolimus existed in an amorphous state in ERG. Tacrolimus release from ERG was attenuated by EC and facilitated by lactose, suggesting that drug release kinetics could adequately be regulated by these components. Those release profiles were consistent with Higuchi's equation, suggesting a diffusion-type release mechanism. Smooth surface of ERG changed to the structure with pores after the release test, likely derived from the dissolution of HPMC and lactose. But ERG structure formed by EC was still maintained after the release test, leading to the longer maintenance of diffusion-type release. Two ERG formulations selected by blood concentration simulation successfully provided long-term retention of tacrolimus in blood in a human absorption study. We successfully developed the formulation exhibiting a significant reduction in Cmax , the longer mean residence time and AUC close to that of an immediate-release tacrolimus formulation, being preferred from the viewpoint of safe and effective immunosuppressant pharmacotherapy.

Tacrolimus in the treatment of myasthenia gravis in patients with an inadequate response to glucocorticoid therapy: randomized, double-blind, placebo-controlled study conducted in China.

BackgroundTo determine the efficacy of low-dose, immediate-release tacrolimus in patients with myasthenia gravis (MG) with inadequate response to glucocorticoid therapy in a randomized, double-blind, placebo-controlled study.MethodsEligible patients had inadequate response to glucocorticoids (GCs) after ⩾6 weeks of treatment with prednisone ⩾0.75 mg/kg/day or 60–100 mg/day. Patients were randomized to receive 3 mg tacrolimus or placebo daily (orally) for 24 weeks. Concomitant glucocorticoids and pyridostigmine were allowed. Patients continued GC therapy from weeks 1–4; from week 5, the dose was decreased at the discretion of the investigator. The primary efficacy outcome measure was a reduction, relative to baseline, in quantitative myasthenia gravis (QMG) score assessed using a generalized linear model; supportive analyses used alternative models.ResultsOf 138 patients screened, 83 [tacrolimus (n = 45); placebo (n = 38)] were enrolled and treated. The change in adjusted mean QMG score from baseline to week 24 was −4.9 for tacrolimus and −3.3 for placebo (least squares mean difference: –1.7, 95% confidence interval: −3.5, −0.1; p = 0.067). A post-hoc analysis demonstrated a statistically significant difference for QMG score reduction of ⩾4 points in the tacrolimus group (68.2%) versus the placebo group (44.7%; p = 0.044). Adverse event profiles were similar between treatment groups.ConclusionsTacrolimus 3 mg treatment for patients with MG and inadequate response to GCs did not demonstrate a statistically significant improvement in the primary endpoint versus placebo over 24 weeks; however, a post-hoc analysis demonstrated a statistically significant difference for QMG score reduction of ⩾4 points in the tacrolimus group versus the placebo group. This study was limited by the low number of patients, the absence of testing for acetylcholine receptor antibody and the absence of stratification by disease duration (which led to a disparity between the two groups).ClinicalTrials.gov identifier: NCT01325571

Pharmacokinetic and pharmacogenetic analysis of immunosuppressive agents after laparoscopic sleeve gastrectomy.

Severe obesity has been shown to limit access to renal transplantation in patients with end-stage renal disease (ESRD). Laparoscopic sleeve gastrectomy (LSG) has been performed in the ESRD population to assist in achieving waitlist and transplant eligibility. Little is known about how LSG impacts the bioequivalence of tacrolimus products and immunosuppression pharmacokinetics. This was a prospective, open-label, single-dose, crossover, two-period pharmacokinetic (PK) study. The purpose of this study was to assess single-dose PK of immediate-release tacrolimus (IR-TAC), extended-release tacrolimus (ER-TAC), and mycophenolic acid (MPA) in adult ESRD patients post-LSG. Twenty-three subjects were included in the 24-hour PK assessments. The ratio of geometric means between ER-TAC and IR-TAC was 103.5% (90% CI; 89.6%-119.6%) for AUC0-24 and 92.5% (90% CI; 80.4%-106.4%) for Cmax . PK parameters were similar between ER-TAC and IR-TAC, except for Cmin (P=.004) and Cmax (P=.04). MPA AUC0-24 was similar when given with either ER-TAC or IR-TAC (P=.32). Patients expressing CYP3A5*1 genotypes had lower tacrolimus AUC0-24 values vs those with CYP3A5*3/*3 (IR-TACP<.001; ER-TACP=.008). Genotype did not impact MPA PK. Dose modification of immunosuppressants post-LSG may not be necessary aside from standard therapeutic drug monitoring.

Immunosuppression with prolonged-release tacrolimus in kidney or liver transplantation in India

Aim: Tacrolimus has proven efficacy as an immunosuppressive therapy to prevent transplant rejection and is widely used as an immediate-release formulation in a twice-daily regimen. Once-daily prolonged-release tacrolimus aims to improve the outcomes by reducing variability in exposure and improving adherence. However, there are limited published data available on prolonged-release tacrolimus in routine clinical practice in India. Methods: This was a Phase IV, multicenter, prospective study of prolonged-release tacrolimus conducted over 12 weeks in adult patients eligible for de novo kidney or liver transplantation in India. Primary efficacy end-point was the event rate of biopsy-confirmed acute rejections (BCARs). Secondary end-points included corticosteroid-resistant rejection incidence, time to first BCAR, graft loss, and death. Safety end-points included renal function, lipid profile, incidence of new-onset diabetes mellitus after transplantation (NODAT), and infection. Results: The study enrolled 92 patients undergoing kidney (81 [88.0%]) or liver transplantation (11 [12.0%]); a total of 76 patients (82.6%) completed the study. Ten kidney transplant patients (overall 10.9%) experienced BCAR. There were seven corticosteroid-sensitive and three corticosteroid-resistant rejections. Median (range) time to kidney transplant rejection was 6.5 (1.0–76.0) days. Renal function was stable or improved. Lipid levels showed a significant increase. Eleven instances of NODAT and seven infections occurred and there were eight deaths (8.7%; six kidney and two liver transplant patients). Conclusions: In de novo kidney and liver transplant recipients in India, prolonged-release tacrolimus was well-tolerated and efficacious with a low incidence of acute rejection. Safety profile was similar to immediate-release tacrolimus from published data.

A Steady-State Head-to-Head Pharmacokinetic Comparison of All FK-506 (Tacrolimus) Formulations (ASTCOFF): An Open-Label, Prospective, Randomized, Two-Arm, Three-Period Crossover Study.

This two‐sequence, three‐period crossover study is the first pharmacokinetic (PK) study to compare all three innovator formulations of tacrolimus (twice‐daily immediate‐release tacrolimus capsules [IR‐Tac]; once‐daily extended‐release tacrolimus capsules [ER‐Tac]; novel once‐daily tacrolimus tablets [LCPT]). Stable renal transplant patients were dosed with each drug for 7 days, and blood samples were obtained over 24 h. Thirty subjects were included in the PK analysis set. A conversion factor of 1:1:0.80 for IR‐Tac:ER‐Tac:LCPT was used; no dose adjustments were permitted during the study. The median (interquartile range) total daily dose was 6.0 (4.0–8.0) mg for IR‐Tac and ER‐Tac and 4.8 (3.3–6.3) for LCPT. Significantly higher exposure on a per milligram basis, lower intraday fluctuation and prolonged time (Tmax) to peak concentration (Cmax) were found for LCPT versus IR‐Tac or ER‐Tac. ER‐Tac showed no differences versus IR‐Tac in exposure, Cmax, Tmax or fluctuation. The observed exposure of IR‐Tac was used to normalize exposure for LCPT and ER‐Tac, resulting in the following recommended total daily dose conversion rates: IR‐Tac:ER‐Tac, +8%; IR‐Tac:LCPT, −30%; ER‐Tac:LCPT, −36%. After exposure normalization, Cmax was ~17% lower for LCPT than for IR‐Tac or ER‐Tac; Cmin was ~6% lower for LCPT compared with IR‐Tac and 3% higher compared with ER‐Tac.

Pharmacokinetics of prolonged-release tacrolimus and implications for use in solid organ transplant recipients.

Prolonged-release tacrolimus was developed as a once-daily formulation with ethylcellulose as the excipient, resulting in slower release and reduction in peak concentration (Cmax ) for a given dose compared with immediate-release tacrolimus, which is administered twice daily. This manuscript reviews pharmacokinetic information on prolonged-release tacrolimus in healthy subjects, in transplant recipients converted from immediate-release tacrolimus, and in de novo kidney and liver transplant recipients. As with the immediate-release formulation, prolonged-release tacrolimus shows a strong correlation between trough concentration (Cmin ) and area under the 24-hour time-concentration curve (AUC24 ), indicating that trough whole blood concentrations provide an accurate measure of drug exposure. We present the pharmacokinetic similarities and differences between the two formulations, so that prescribing physicians will have a better understanding of therapeutic drug monitoring in patients receiving prolonged-release tacrolimus.

A cost-utility analysis of prolonged-release tacrolimus relative to immediate-release tacrolimus and ciclosporin in liver transplant recipients in the UK

Background: Calcineurin inhibitors (CNIs) represent the cornerstone of immunosuppressive therapy after liver transplantation. A recent network meta-analysis (NMA) evaluated the relative efficacy of CNIs ciclosporin, prolonged-release (PR) tacrolimus, and immediate-release (IR) tacrolimus in adult liver transplant recipients based on randomized and large observational trials published since 2000. Based on the NMA findings, the present study evaluated the cost-utility of PR tacrolimus relative to ciclosporin or IR tacrolimus in liver transplant recipients in the UK.Methods: A Markov model was developed to evaluate the cost-utility of immunosuppressive regimens in liver transplant recipients, capturing costs associated with immunosuppression, retransplantation, acute rejection (AR), and cytomegalovirus infection. Mortality, graft loss, and AR odds ratios were derived from the NMA. Costs were taken from the British National Formulary and the NHS National Tariff and expressed in 2016 pounds sterling. Future costs and effects were discounted at 3.5% annually.Results: Over 25 years, PR tacrolimus resulted in increased life expectancy and quality-adjusted life expectancy (QALE) relative to IR tacrolimus and ciclosporin. Relative to ciclosporin, QALE increased by 1.17 quality-adjusted life years (QALYs) with PR tacrolimus while costs increased by GBP £4645, yielding an incremental cost-effectiveness ratio (ICER) of £3962 per QALY gained. Relative to IR tacrolimus, QALE increased by 0.78 QALYs and costs by £1474, resulting in an ICER of £1889 per QALY gained. Sensitivity analysis showed the analysis to be most sensitive to dosing assumptions.Conclusions: Based on a UK-specific analysis of the projected cost-utility of PR tacrolimus relative to IR tacrolimus and ciclosporin, PR tacrolimus was cost-effective, improving life expectancy and QALE relative to both IR tacrolimus and ciclosporin, yielding ICERs below £20 000 per QALY gained. The main limitations of the study were data source heterogeneity and omitting the economic and clinical effects of treating aspects of recurrent liver disease.

Evaluating the Cost-Effectiveness of Prolonged-Release Tacrolimus Relative to Immediate-Release Tacrolimus in Liver Transplant Patients Based on Data from Routine Clinical Practice.

BackgroundAs of 2014, there were approximately 8300 patients with a functioning liver transplant in the UK Transplant Registry, with 880 liver transplants performed in 2013–2014 alone. Tacrolimus, typically used in combination with steroids and mycophenolate mofetil, currently represents the cornerstone of post-transplant immunosuppression in liver transplant recipients.ObjectivesThe objective of the present study was to evaluate the cost-effectiveness of prolonged-release (PR) tacrolimus (Advagraf®, Astellas Pharma Inc., Tokyo, Japan) versus branded immediate-release (IR) tacrolimus (Prograf®, Astellas Pharma Inc., Tokyo, Japan) in liver transplant recipients in the UK.MethodsA model was developed in Microsoft Excel to estimate costs associated with immunosuppressive medications and retransplantation. Three-year patient and graft survival data were taken from a recent retrospective registry analysis and dose data were taken from prescribing information. Costs in 2014 pounds sterling were taken from the British National Formulary and the National Health Service National Tariff.ResultsOver a 3-year time horizon, the numbers needed to treat with PR tacrolimus relative to IR tacrolimus were 14 to avoid one graft loss and 18 to avoid one death. The model was sensitive to dosing assumptions, with incremental cost estimates varying between a saving of £1642 (standard deviation £885) per patient, assuming the same per-kilogram dosing of PR tacrolimus (Advagraf®) and IR tacrolimus (Prograf®) and an increase of £1350 (£964) using RCT dose data.ConclusionData from a recent analysis of routine clinical practice data in liver transplant recipients on PR tacrolimus and IR tacrolimus showed significant differences in long-term graft survival in favor of PR tacrolimus. Modeling these data in the UK showed that, over a 3-year time horizon, one graft would be saved for every 14 patients treated with PR tacrolimus with minimal impact on costs when compared with branded IR tacrolimus (Prograf®).

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.

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.

PGI2 - Bayesian Hierarchical modeling of randomized and non-randomized studies comparing ciclosporin with immediate- and prolonged-release tacrolimus in Liver Transplant Recipients

Several meta-analyses comparing ciclosporin with immediate-release (IR) tacrolimus have been conducted. Only recently have sufficient data become available for evidence synthesis including prolonged-release (PR) tacrolimus. In the present study, a network meta-analysis (NMA) was conducted to compare the efficacy of ciclosporin, IR and PR tacrolimus in liver transplant recipients. Systematic literature review of PubMed, EMBASE and the Cochrane Library identified randomized controlled trials and large-scale observational studies (≥500 patients) published since January 2000 comparing IR tacrolimus with PR tacrolimus or ciclosporin following primary liver transplant. A Bayesian NMA was conducted to evaluate likelihood of death, graft loss, and acute rejection (AR) at 12 months. Outcomes were adjusted for recipient gender and age, hepatitis C (HCV) status, hepatocellular carcinoma, mycophenolate mofetil, azathioprine, and steroid use. Head-to-head study results were available for ciclosporin versus IR tacrolimus (n=14) and PR tacrolimus versus IR tacrolimus (n=2). Relative to ciclosporin, IR and PR tacrolimus were associated with reduced likelihood of death within 12 months of transplant (median odds ratios [OR] of 0.78 and 0.60, respectively). Mortality outcomes were superior with PR versus IR tacrolimus (median OR of 0.76). AR was less common with IR tacrolimus compared with ciclosporin (median OR of 0.69), whereas limited data for PR tacrolimus was evidenced by large credible intervals. There were no significant differences with respect to graft loss. Sensitivity analyses indicated that results were robust to assumptions and changes in confounders. Confounder analysis found that patient age was associated with death, whereas HCV status was associated with AR and graft loss. Patient and treatment factors beyond immunosuppressive treatment influence outcomes. Results of this confounder-controlled analysis provide further evidence that tacrolimus has substantial benefits over ciclosporin in liver transplant recipients. Compared with IR tacrolimus, data indicate that PR tacrolimus is superior with respect to patient survival.

PGI3 - Systematic literature review, meta-analysis and indirect treatment comparison of prolonged-release tacrolimus relative to ciclosporin and immediate-release tacrolimus as the primary immunosuppressive regimen in Liver Transplant Recipients

PGI3 - Systematic literature review, meta-analysis and indirect treatment comparison of prolonged-release tacrolimus relative to ciclosporin and immediate-release tacrolimus as the primary immunosuppressive regimen in Liver Transplant Recipients

A UK analysis of the cost of switching renal transplant patients from an immediate-release to a prolonged-release formulation of tacrolimus based on differences in trough concentration variability

Background and aims:Randomized controlled trials have shown that a once-daily prolonged-release (PR) tacrolimus formulation (PR tacrolimus; Advagraf), is non-inferior to a twice-daily immediate-release (IR) tacrolimus formulation (IR tacrolimus; Prograf) in terms of biopsy-proven acute rejection, graft failure and mortality in renal transplant recipients. However, relative to IR tacrolimus, PR tacrolimus exhibits reduced tacrolimus trough concentration variability, which has been associated with reduced graft failure. Based on these data, the present study evaluated the cost of switching UK renal transplant patients from IR tacrolimus to PR tacrolimus.Methods:UK-specific data on acute rejection, graft failure, and mortality were used to construct a budget impact model to assess the costs of switching from IR tacrolimus to PR tacrolimus on a 1:1 mg:mg basis. The model assumed that 3.1% of patients on PR tacrolimus had high tacrolimus trough concentration variability compared with 17.4% on IR tacrolimus, based on a study comparing PR tacrolimus and IR tacrolimus pharmacokinetics. A relative graft failure risk of 2.38 was applied to high variability patients based on data from a tacrolimus variability study in which 10/148 patients with low variability experienced graft failure, compared with 24/149 in the high variability group. Cost data were taken from the British National Formulary and 2012–2013 NHS tariff information.Results:The mean per-patient cost (including tacrolimus, concomitant immunosuppressive medications, dialysis after graft failure, and treatment for acute rejection) was GBP 26,941 (standard deviation [SD] = GBP 2765) with PR tacrolimus vs GBP 30,356 (SD = GBP 3085) for IR tacrolimus over a 5-year period, corresponding to a saving of GBP 3415 (SD = GBP 516) per patient or GBP 341,500 in a hypothetical 100-patient transplant center. Cost savings were driven primarily by lower dialysis costs resulting from the lower proportion of PR tacrolimus patients with high tacrolimus trough concentration variability (leading to lower graft failure risk).Limitations:The main limitation of the study was the use of heterogeneous data sources to capture the effect of within-patient variability on graft failure. The most important difference between the studies was the definition of the threshold between low and high within-patient variability. This was explored in sensitivity analyses in which the inter-arm difference in the inter-arm proportions of patients with high and low variability was abolished.Conclusions:Converting UK renal transplant recipients from IR tacrolimus to PR tacrolimus was associated with lower pharmacy and dialysis costs.