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

Tremblay, Sylvie; Nigro, V.; Weinberg, Joanne; Woodle, E. Steve; Alloway, Rita R.

doi:10.1111/ajt.13935

Cited by 125 publications

(184 citation statements)

References 32 publications

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“…Study data from maintenance patients are in accordance with our data 9. The direct comparison of LCPT with IR-Tac in the LCP-Tacro 3002 trial has been biased by the FDA-guided decision to start IR-Tac with a total daily dose of only 0.1 mg/kg (LCPT: 0.17 mg/kg).This led to frequent dose escalations in IR-Tac-patients, whereas patients on LCPT rarely required higher doses.ER-Tac has been started with 0.2 mg/kg, and trough level measurements regularly led to dose escalations (and at least 1 extra dose with IR-Tac in a subset of 12/36 patients).…”

supporting

confidence: 77%

Bioavailability and costs of once‐daily and twice‐daily tacrolimus formulations in de novo kidney transplantation

Glander

Waiser

Kasbohm

et al. 2018

Clinical Transplantation

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The use of once-daily tacrolimus in de novo kidney transplantation is increasingly common. Therefore, we were interested in bioavailability aspects of novel once-daily tacrolimus (LCPT, Envarsus) and once-daily tacrolimus extended-release formulation (ER-Tac, Advagraf) compared with twice-daily immediate-release tacrolimus (IR-Tac, Prograf). Furthermore, we calculated the costs. Kidney allograft recipients on tacrolimus-based immunosuppression within 2 clinical trials were included in a single-center analysis. The tacrolimus formulations were compared with respect to daily doses, doses per body weight, trough levels, and concentration-dose (C/D) ratio over 12 months. Intrapatient variability in trough levels and C/D ratios after 3 months was calculated. For the calculation of tacrolimus costs, German list prices were used. Eighty patients (21 with LCPT, 23 with IR-Tac, and 36 with ER-Tac) were analyzed. Pharmacokinetic comparisons revealed significantly higher bioavailability of LCPT at all visits. The variability of trough levels and C/D ratios in general was high and highest in LCPT patients. Different dose requirements translated into different costs. Median treatment costs during the first year were 7.825€ (IQR 6.195-8.892€) for LCPT, 9.813€ (IQR 7.630-16.832€) for IR-Tac, and 9.838€ (IQR 7.503- 13.541€) for ER-Tac (Kruskal-Wallis test, P = .003). The 3 tacrolimus formulations exhibit different dose requirements, exposure, and costs in favor of LCPT.

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supporting

confidence: 77%

Bioavailability and costs of once‐daily and twice‐daily tacrolimus formulations in de novo kidney transplantation

Glander

Waiser

Kasbohm

et al. 2018

Clinical Transplantation

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“…Recently, Tremblay and colleagues compared all 3 formulations of tacrolimus (IR-Tac, PR-Tac, and ER-Tac) in 30 stable renal transplant recipients. 20 Patients were dosed with each drug for 7 days, and blood samples were obtained over 24 hours. A conversion factor of 1:1:0.80 for IR-Tac:PR-Tac:ER-Tac was used; no dose adjustments were permitted during the study.…”

Section: Discussionmentioning

confidence: 99%

Untitled

Altieri¹,

Delaval²,

Kimmoun³

et al. 2018

Exp Clin Transplant

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Objectives: After organ transplant, strategies to simplify the therapeutic regimen may improve adherence and prevent rejection and/or graft loss. The aim of the present study was to evaluate the safety of conversion from once-daily prolonged-release tacrolimus (Advagraf; Astellas Pharma Europe Limited, Middlesex, UK) to once-daily extended-release tacrolimus (Envarsus; Chiesi SAS, Nanterre, France) in stable adult liver transplant recipients. Materials and Methods: This observational study included 44 liver transplant patients (median age of 59 y; 63.6% men; median delay after transplant of 72.5 mo). Conversion was based on a 1:0.70 proportion. Results: Mean dose of tacrolimus was 2.65 ± 1.24 mg/day before conversion and 2.09 ± 1.68 mg/day after conversion (P < .05), with ratio of 1:0.79. Mean serum tacrolimus trough level increased after conversion (4.92 ± 1.65 vs 5.60 ± 2.89 ng/mL; P < .05), with ratio of 1:1.14. Six months after conversion, mean dose of tacrolimus was 1.65 ± 0.93 mg/day (ratio of 1:0.62) and mean serum tacrolimus trough level was 4.82 ± 1.85 ng/mL, similar to the initial level before conversion. At the end of follow-up, 2 patients had returned to once-daily prolonged-release tacrolimus because of adverse effects (allergy, digestive trouble), which resolved thereafter. The mean cost of tacrolimus therapy was 5.54 ± 2.29 Euros/patient/day before conversion and 4.11 ± 2.32 Euros/patient/day after conversion (P < .05). Conclusions:Conversion from prolonged-release to extended-release tacrolimus in stable liver transplant patients is safe and cost-effective; however, initially, dose adaptations and careful monitoring are required.

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“…The authors found that anti-tumor necrosis factor (anti-TNF) biologics were more likely to achieve mucosal healing than placebo in Crohn's disease (CD) and both anti-TNFs and vedolizumab had higher rates of mucosal healing compared to pla- remains to be determined and validated in prospective studies. 6,7 Last, the optimal time-point to measure mucosal healing for biologics is also unclear, as the time to achieve mucosal healing likely may vary depending on a medication's mode of delivery or mechanism of action.…”

Section: -4mentioning

confidence: 99%

“…6,7 As previously shown, MRS is better than histology in assessing quantitative changes in liver fat in a trial. 8 Despite the short study period, inclusion of MR elastography could have provided valuable additional information as fibrosis stage has been demonstrated to be the most important predictor of morbidity and mortality in NAFLD.…”

mentioning

confidence: 91%

Editorial: tacrolimus―how low can you go?

O’Leary¹

2017

Aliment Pharmacol Ther

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content using MRS, the primary outcome, in intention-to-treat analysis. There was also a modest but statistically significant improvement in body mass index in the high-dose group compared to placebo. Patients included in the trial were primarily middle-aged, nondiabetic, men of South Korean descent limiting its generalisability to other populations. In addition, despite block randomisation the high-dose oltipraz group had the most liver fat content at baseline 38.8% vs 29.9% in the placebo group and this difference across groups was statistically significant, P=.02. In small clinical trials, stratified block randomisation or adaptive randomisation may help to avoid asymmetry in critical variables. To mitigate concern that the benefit in the oltipraz group may have been impacted by the degree of steatosis at baseline, the authors presented per cent change from baseline in liver fat and showed a trend towards improvement in the low-dose oltipraz group, which supports the compound's efficacy.The authors' chose to utilise MRS as the primary endpoint adding to a growing number of trials. transplant recipients >1 year after transplant from twice daily oral to sublingual tacrolimus. Despite its small sample size, the crossover nature, varied indication for transplant and pharmacokinetic sampling make this a well-done study. They convincingly show that sublingual administration results in a 37% lower dose of tacrolimus to achieve a similar trough concentration and AUC while the 2 hour peak concentration was significantly lower. Although not shown in this study,we would hope that a lower C MAX may lead to fewer side effects, while the maintenance of AUC and trough were shown to achieve similar efficacy.Fortunately, no patient experienced rejection or graft loss during the study, and the ability to cut the dose by one-third through sublingual administration and yet maintain the AUC and trough concentration is an attractive cost saving approach. Of note, standard twice-daily orally administered tacrolimus has been used once-daily. 3This cut the amount of medication needed to 85% of the total daily dose and achieved the same AUC and trough concentration but is not FDA approved. It is unknown if the dose of sublingual tacrolimus might further be lowered if it were administered once-daily.Although well done, the study's small sample size, absence of side effect assessment, maintenance of twice daily dosing and lack of truly long-term follow-up only allow us to conclude that once daily administration should next be evaluated. You ask: How low can you go? We unfortunately maintain a one-size fits all immunosuppression strategy for transplant patients.However, as we transplant older, sicker patients with more comorbid conditions we must strive to utilize drugs with better bioavailability to improve dosing schedules, reliability of levels, minimize side effects and optimize cost. Achieving a high level of compliance with any tacrolimus regimen will always be the most important factor in long-term rejection-free graft survival. M...

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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

Cited by 125 publications

References 32 publications

Bioavailability and costs of once‐daily and twice‐daily tacrolimus formulations in de novo kidney transplantation

Bioavailability and costs of once‐daily and twice‐daily tacrolimus formulations in de novo kidney transplantation

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Editorial: tacrolimus―how low can you go?

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