Conversion from Prograf to Advagraf in stable paediatric renal transplant patients and 1-year follow-up

Sansuán, Antonio J. Carcas; Espinosa-Román, Laura; Almeida-Paulo, Gonzalo N.; Alonso-Melgar, Ángel; Garcı́a-Meseguer, C; Fernández-Camblor, Carlota; Medrano, Nicolás; Ramı́rez, Elena

doi:10.1007/s00467-013-2564-y

Cited by 13 publications

(29 citation statements)

References 23 publications

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“…We found that renal function was stable in both kidney and liver transplant recipients after conversion from immediate‐ to prolonged‐release tacrolimus, in accordance with previous studies . Collectively, the efficacy data presented here suggest that conversion from immediate‐ to prolonged‐release tacrolimus is associated with a very low AR rate over 1 year in solid organ transplant recipients.…”

Section: Discussionsupporting

confidence: 90%

“…In this study, only two (2.5%) kidney transplant recipients experienced AR, and there were no deaths or graft losses. These data are aligned with previous reports of pediatric kidney and liver transplant recipients converted from immediate‐ to prolonged‐release tacrolimus, in whom ARs were very low, or absent, over follow‐up periods ranging from 6 months to 5 years . For example, in a study of 11 pediatric stable kidney transplant recipients converted from immediate‐ to prolonged‐release tacrolimus, there were two BCAR episodes in one patient during the 1‐year follow‐up period .…”

Section: Discussionsupporting

confidence: 86%

“…Evidence from clinical studies suggests that prolonged‐release tacrolimus is effective and well tolerated in adult transplant recipients converted from the immediate‐release formulation . From the small number of published studies, efficacy and safety outcomes in pediatric kidney and liver transplant recipients converted from immediate‐ to prolonged‐release tacrolimus were generally comparable to those in adult transplant patients . Indeed, Heffron et al .…”

Section: Introductionmentioning

confidence: 99%

“… found no episodes of acute rejection (AR), graft loss, or death in an open‐label study of 18 stable pediatric liver transplant recipients over a 1‐year period after conversion from immediate‐ to prolonged‐release tacrolimus. Furthermore, there were no severe drug‐related adverse events (AEs) and no significant changes in renal function reported in a 1‐year follow‐up open‐label study of 21 pediatric kidney transplant recipients following conversion from immediate‐ to prolonged‐release tacrolimus .…”

Section: Introductionmentioning

confidence: 99%

“…Clinical experience with prolonged‐release tacrolimus is limited in pediatric solid organ transplant recipients and reported data are generally from small patient numbers . Therefore, we undertook this study to assess the pharmacokinetics, efficacy, and safety of prolonged‐release tacrolimus over a 1‐year period in a large cohort of pediatric kidney, liver, and heart transplant recipients following conversion from immediate‐release tacrolimus.…”

Section: Introductionmentioning

confidence: 99%

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Efficacy and safety of prolonged‐release tacrolimus in stable pediatric allograft recipients converted from immediate‐release tacrolimus – a Phase 2, open‐label, single‐arm, one‐way crossover study

Rubik

Debray

Kelly³

et al. 2019

Transpl Int

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Summary There are limited clinical data regarding prolonged‐release tacrolimus (PR‐T) use in pediatric transplant recipients. This Phase 2 study assessed the efficacy and safety of PR‐T in stable pediatric kidney, liver, and heart transplant recipients (aged ≥5 to ≤16 years) over 1 year following conversion from immediate‐release tacrolimus (IR‐T), on a 1:1 mg total‐daily‐dose basis. Endpoints included the incidence of acute rejection (AR), a composite endpoint of efficacy failure (death, graft loss, biopsy‐confirmed AR, and unknown outcome), and safety. Tacrolimus dose and whole‐blood trough levels (target 3.5–15 ng/ml) were also evaluated. Overall, 79 patients (kidney, n = 48; liver, n = 29; heart, n = 2) were assessed. Following conversion, tacrolimus dose and trough levels remained stable; however, 7.6–17.7% of patients across follow‐up visits had trough levels below the target range. Two (2.5%) patients had AR, and 3 (3.8%) had efficacy failure. No graft loss or deaths were reported. No new safety signals were identified. Drug‐related treatment‐emergent adverse events occurred in 28 patients (35.4%); most were mild, and all resolved. This study suggests that IR‐T to PR‐T conversion is effective and well tolerated over 1 year in pediatric transplant recipients and highlights the importance of therapeutic drug monitoring to maintain target tacrolimus trough levels.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionsupporting

confidence: 86%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Efficacy and safety of prolonged‐release tacrolimus in stable pediatric allograft recipients converted from immediate‐release tacrolimus – a Phase 2, open‐label, single‐arm, one‐way crossover study

Rubik

Debray

Kelly³

et al. 2019

Transpl Int

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

Staatz

Tett

2015

Clin Pharmacokinet

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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 24 h (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 a...

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Predictive engines based on pharmacokinetics modelling for tacrolimus personalized dosage in paediatric renal transplant patients

Prado-Velasco

Borobia

Carcas-Sansuan

2020

Sci Rep

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The development of predictive engines based on pharmacokinetic-physiological mathematical models for personalised dosage recommendations is an immature field. Nevertheless, these models are extensively applied during the design of new drugs. This study presents new advances in this subject, through a stable population of patients who underwent kidney transplantation and were prescribed tacrolimus. We developed 2 new population pharmacokinetic models based on a compartmental approach, with one following the physiologically based pharmacokinetic approach and both including circadian modulation of absorption and clearance variables. One of the major findings was an improved predictive capability for both models thanks to the consideration of circadian rhythms, both in estimating the population and in Bayesian individual customisation. This outcome confirms a plausible mechanism suggested by other authors to explain circadian patterns of tacrolimus concentrations. We also discovered significant intrapatient variability in tacrolimus levels a week after the conversion from a fast-release (Prograf) to a sustained-release formulation (Advagraf) using adaptive optimisation techniques, despite high adherence and controlled conditions. We calculated the intrapatient variability through parametric intrapatient variations, which provides a method for quantifying the mechanisms involved. We present a first application for the analysis of bioavailability changes in formulation conversion. The 2 pharmacokinetic models have demonstrated their capability as predictive engines for personalised dosage recommendations, although the physiologically based pharmacokinetic model showed better predictive behaviour.

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Conversion from Prograf to Advagraf in stable paediatric renal transplant patients and 1-year follow-up

Abstract: Our results show that Advagraf bioequivalence cannot be ensured in this population. Significant changes in tacrolimus levels and dose were observed on long-term follow-up.

Cited by 13 publications

References 23 publications

Efficacy and safety of prolonged‐release tacrolimus in stable pediatric allograft recipients converted from immediate‐release tacrolimus – a Phase 2, open‐label, single‐arm, one‐way crossover study

Efficacy and safety of prolonged‐release tacrolimus in stable pediatric allograft recipients converted from immediate‐release tacrolimus – a Phase 2, open‐label, single‐arm, one‐way crossover study

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

Predictive engines based on pharmacokinetics modelling for tacrolimus personalized dosage in paediatric renal transplant patients

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