Converting immunosuppression from an oral suspension to a granule formulation of tacrolimus in pediatric renal transplant recipients.

OS of tacrolimus prepared from tacrolimus powder is not licensed for children. A licensed GF for OS allows flexibility for body weight-based dose adjustments. This study aimed at exploring the efficacy of conversion from OS to the GF of tacrolimus in stable pediatric renal transplant recipients. Records of 25 pediatric renal transplant recipients aged under 18 years who were switched from an unlicensed tacrolimus OS to GF were reviewed. At day 0, 1 week, and 4-8 weeks post-conversion, there were no differences regarding daily tacrolimus dose (3.4 ± 3 vs 3.5 ± 2.9 vs 3.5 ± 2.9 mg/day), trough tacrolimus levels (4.5 ± 2.7 vs 4.2 ± 2.7 vs 4.4 ± 3.1 ng/mL), dose-normalized trough tacrolimus levels (1.7 ± 1.1 vs 1.5 ± 1.0 vs 1.7 ± 1.3 ng/mL/mg), PCr (65.6 ± 29.4 vs 67.9 ± 30.4 vs 69.8 ± 27.9 µmol/L), and eGFR (73 ± 24.9 vs 68.7 ± 20.2 vs 65.5 ± 18.2 mL/min/1.73 m2 ) (P > .05). GF dose adjustment was required in 52% of participants. Eighty-eight percent of patients had to return for repeat tacrolimus levels following dose modifications, generating 33 extra visits (≥2 extra visits for 1/3 of subjects). No rejection episodes occurred in the year after conversion. In conclusion, conversion from tacrolimus OS to GF in stable pediatric renal transplant recipients is safe and efficacious. However, close therapeutic drug monitoring in the immediate post-conversion period is necessary.

Switching STudy of Kidney TRansplant PAtients with Tremor to LCP-TacrO (STRATO): an open-label, multicenter, prospective phase 3b study.

Tremor is a common side effect of tacrolimus correlated with peak-dose drug concentration. LCPT, a novel, once-daily, extended-release formulation of tacrolimus, has a reduced Cmax with comparable AUC exposure, requiring a ~30% dose reduction vs. immediate-release tacrolimus. In this phase 3b study, kidney transplant recipients (KTR) on a stable dose of tacrolimus and with a reported clinically significant tremor were offered a switch to LCPT. Tremor pre- and seven d post-conversion was evaluated by independent, blinded movement disorder neurologists using the Fahn-Tolosa-Marin (FTM) scale and by an accelerometry device; patients completed the QUEST (quality of life in essential tremor) and the Patient Global Impression of Change. There were 38 patients in the mITT population. A statistically and clinically significant improvement in tremor (FTM score, amplitude as measured by the accelerometry device and QOL [p-values < 0.05]) resulted post-conversion. Change in QUEST was significantly (p = 0.006) correlated (R = 0.44) with change in FTM; 78.9% of patients reported an improvement after switching to LCPT (p < 0.0005). To our knowledge this is the first trial in KTR that utilizes a sophisticated and reproducible measurement of tremor. Results suggest LCPT is associated with clinically meaningful improvement of hand tremor and may be an alternative management approach in lieu of further dose reduction of immediate-release tacrolimus for patients experiencing tremor.

A multi-center interventional study to assess pharmacokinetics, effectiveness, and tolerability of prolonged-release tacrolimus after pediatric kidney transplantation: study protocol for a prospective, open-label, randomized, two-phase, two-sequence, single dose, crossover, phase III b trial.

Background: Tacrolimus, a calcineurin inhibitor (CNI), is currently the first-line immunosuppressive agent in kidney transplantation. The therapeutic index of tacrolimus is narrow due to due to the substantial impact of minor variations in drug concentration or exposure on clinical outcomes (i.e., nephrotoxicity), and it has a highly variable intra- and inter-individual bioavailability. Non-adherence to immunosuppressants is associated with rejection after kidney transplantation, which is the main cause of long-term graft loss. Once-daily formulations have been shown to significantly improve adherence compared to twice-daily dosing. Envarsus®, the once-daily prolonged-release formulation of tacrolimus, offers the same therapeutic efficacy as the conventional twice-daily immediate-release tacrolimus formulation (Prograf®) with improved bioavailability, a more consistent pharmacokinetic profile, and a reduced peak to trough, which may reduce CNI-related toxicity. Envarsus® has been approved as an immunosuppressive therapy in adults following kidney or liver transplantation but has not yet been approved in children. The objective of this study is to evaluate the pharmacokinetic profile, efficacy, and tolerability of Envarsus® in children and adolescents aged ≥ 8 and ≤ 18 years to assess its potential role as an additional option for immunosuppressive therapy in children after kidney transplantation. Methods/design: The study is designed as a randomized, prospective crossover trial. Each patient undergoes two treatment sequences: sequence 1 includes 4 weeks of Envarsus® and sequence 2 includes 4 weeks of Prograf®. Patients are randomized to either group A (sequence 1, followed by sequence 2) or group B (sequence 2, followed by sequence 1). The primary objective is to assess equivalency between total exposure (of tacrolimus area under the curve concentration (AUC0-24)), immediate-release tacrolimus (Prograf®) therapy, and prolonged-release tacrolimus (Envarsus®) using a daily dose conversion factor of 0.7 for prolonged- versus immediate-release tacrolimus. Secondary objectives are the assessment of pharmacodynamics, pharmacogenetics, adherence, gut microbiome analyses, adverse events (including tacrolimus toxicity and biopsy-proven rejections), biopsy-proven rejections, difference in estimated glomerular filtration rate (eGFR), and occurrence of donor-specific antibodies (DSAs). Discussion: This study will test the hypothesis that once-daily prolonged-release tacrolimus (Envarsus®) is bioequivalent to twice-daily intermediate-release tacrolimus after pediatric kidney transplantation and may reduce toxicity and facilitate medication adherence. This novel concept may optimize immunosuppressive therapy for more stable graft function and increased graft survival by avoiding T-cell mediated and/or antibody-mediated rejection due to improved adherence. In addition, the study will provide data on the pharmacodynamics and pharmacogenetics of prolonged-release tacrolimus in children and adolescents. Clinical Trial Registration: EUDRA-CT 2019-003710-13 and ClinicalTrial.gov, identifier NCT06057545.

A randomized, crossover pharmacokinetic study comparing generic tacrolimus vs. the reference formulation in subpopulations of kidney transplant patients.

An exploratory, post hoc analysis was performed using data from a prospective, multicenter, open-label, randomized, two-period (14 d per period), two-sequence, crossover, steady-state pharmacokinetic study comparing generic tacrolimus (Sandoz) vs. reference tacrolimus in stable renal transplant patients receiving their pre-study twice-daily dose. Pharmacokinetic parameters were compared in 68 patients according to gender, African American ethnicity, the presence or absence of diabetes, and use of steroids. The ratios of tacrolimus AUC0-12 h , Cmax , and C12 with generic vs. reference tacrolimus were calculated using the geometric mean (GM) of dose-normalized values at days 14 and 28. Mean (SD) tacrolimus dose at baseline was 5.7 (4.2) mg/d. There were no consistent differences in dose-normalized AUC0-12 h , C12 , Cmax, or tmax between the generic and reference preparations within subpopulations. The 90% confidence intervals (CI) for the ratios of dose-normalized AUC0-12 h and C12 with generic vs. reference tacrolimus were within 80-125% for all subpopulations, as were 90% CIs for Cmax other than for females, African Americans, and non-diabetics, which is not unexpected given the wide variability of tacrolimus Cmax and the small subpopulation sizes. These exploratory results suggest that this generic tacrolimus preparation would be expected to offer comparable bioavailability to the reference drug in these patient subpopulations.

Impact of Once- Versus Twice-Daily Tacrolimus Dosing on Medication Adherence in Stable Renal Transplant Recipients: A Canadian Single-Center Randomized Controlled Trial.

BACKGROUND: Prevalence of immunosuppressant nonadherence in renal transplant recipients is high despite negative clinical outcomes associated with nonadherence. Simplification of dosing has been demonstrated to improve adherence in renal transplant recipients as measured through electronic monitoring and self-report. OBJECTIVE: The purpose of this study was to replicate and extend previous findings by measuring adherence with multiple methods in a Canadian sample. DESIGN: The study design was a randomized controlled medication dosing trial in adult renal transplant patients. The trial length was 4 months. SETTING: This study was conducted within the Solid Organ Transplant (SOT) Clinic at Vancouver General Hospital (VGH; Vancouver, Canada). PATIENTS: A total of 46 adult renal recipients (at least 1 year post-transplant) were recruited through the SOT clinic. With 8 withdrawals, 38 individuals completed all phases of the study. MEASUREMENTS: Medication adherence was measured for a period of 4 months using multiple methods, including electronic monitoring (MEMS [Medication Event Monitoring System]), pharmacy refill data (medication possession ratio [MPR]), and by self-report using the Adherence subscale of the Transplant Effects Questionnaire (TEQ). METHODS: Participants were randomized to twice-daily (n = 19) or once-daily tacrolimus dosing (n = 19) and followed over a 4-month period via monthly clinic study visits. Comparisons between the treatment groups were performed using the Mann-Whitney U and chi-square tests, for continuous and categorical variables, respectively. RESULTS: As outlined in Table 3, the once-daily dosing group showed significantly better MEMS Dose Adherence (P = .001), whereas MEMS Timing Adherence showed a tendency toward better adherence for this group, but was not significant (P = .052). MEMS Days Adherent (P = .418), MPR% (P = .123), and self-reported adherence (P = .284) did not differ between the once- and twice-daily dosing groups when measured as continuous variables. The MPR% was significantly better for the once-daily dosing group when measured dichotomously but not continuously (P = .044). Notably, most of those exposed to once-daily dosing (63.2%) preferred this to the twice-daily regimen. LIMITATIONS: Limitations included small sample size and short follow-up period, precluding the examination of clinical outcome differences. CONCLUSIONS: Results for dose adherence replicate the finding that dose simplification increases adherence to immunosuppressants as measured through electronic monitoring. Such an advantage for the once-daily dosing group was not seen across the 2 other electronic monitoring measurement variables (days and timing adherence). This study extends previous research by examining adherence in once versus twice-daily dosing via prescription refill data in a Canadian sample. Given the gravity of potential health outcomes associated with nonadherence, although results indicate inconsistencies in significance testing across measurement methods, the medium to large effect sizes seen in the data favoring better adherence with once-daily dosing provide an indication of the potential clinical significance of these findings. TRIAL REGISTRATION: This study was registered with ClinicalTrials.gov (NCT01334333) on April 11, 2011.

CONTEXTE: Bien que la non-observance du traitement immunosuppresseur soit associée à de mauvais résultats cliniques, sa prévalence demeure élevée chez les receveurs d'une greffe rénale. Il a été démontré qu'une posologie simplifiée améliorait l'observance thérapeutique mesurée par suivi électronique et auto-évaluation dans cette population. OBJECTIF: Cette étude visait à reproduire et à élargir les résultats d'études précédentes en mesurant par différentes méthodes l'observance thérapeutique dans un échantillon de patients canadiens. TYPE D'ÉTUDE: Un essai contrôlé à répartition aléatoire d'une durée de quatre mois examinant la posologie médicamenteuse d'adultes greffés rénaux. CADRE: L'étude s'est tenue au sein de la Solid Organ Transplant Clinic (clinique SOT) du Vancouver General Hospital (VGH; Vancouver, Canada). SUJETS: Quarante-six greffés rénaux adultes ont été recrutés (au moins un an post-transplantation) par l'entremise de la clinique SOT. En raison de huit retraits, l'étude porte sur trente-huit individus ayant complété toutes les phases de l'étude. MESURES: L'observance thérapeutique a été mesurée sur une période de quatre mois, selon différentes méthodes, notamment le suivi électronique (MEMS), le renouvellement des ordonnances (rapport de possession de médicaments­RPM) et l'auto-évaluation avec la sous-échelle d'observance du Transplant Effects Questionnaire (TEQ). MÉTHODOLOGIE: Les participants ont été répartis aléatoirement pour recevoir du tacrolimus deux fois par jour (n = 19) ou une fois par jour (n = 19) et ont été suivis pendant quatre mois au moyen de visites mensuelles à la clinique. Les comparaisons entre les groupes de traitement ont été effectuées par tests U de Mann-Whitney (variables continues) et tests de chi-deux (variables nominales). RÉSULTATS: Comme indiqué dans le tableau 3, lorsque l'observance est mesurée par MEMS, le groupe ayant reçu une dose quotidienne unique a montré une observance nettement supérieure au niveau de la dose (P = 0.001), de même qu'une tendance vers une meilleure observance du traitement au niveau du moment, quoique cette dernière ne soit pas significative (P = 0.052). Le nombre de jours d'observance mesuré par MEMS (P = 0.418), le pourcentage RPM (P = 0.123) et l'observance auto-déclarée (P = 0.284) n'ont pas différé entre les groupes lorsque mesurés comme variables continues. Le pourcentage RPM était significativement plus élevé pour le groupe traité une fois par jour, lorsque mesuré de façon dichotomique, mais non continue (P = 0.044). La majorité des patients traités par une dose unique quotidienne (63.2%) ont préféré ce schéma posologique à une prise deux fois par jour. LIMITES: La petite taille de l'échantillon et la courte période de suivi empêchent l'examen des différences observées dans les résultats cliniques. CONCLUSION: Les résultats sur l'observance de la dose reproduisent la conclusion selon laquelle un dosage simplifié augmenterait l'observance du traitement immunosuppresseur, lorsque mesurée par MEMS. Un tel avantage pour le groupe recevant une dose quotidienne unique n'a pas été observé pour les deux autres variables de mesure par MEMS (observance en jours et du moment de la prise du médicament). La présente étude élargit les recherches antérieures en examinant l'observance de la posologie (une ou deux fois par jour) avec les données de renouvellement des ordonnances dans un échantillon canadien. Compte tenu de la gravité des effets potentiels de la non-observance thérapeutique sur la santé, et bien que les résultats indiquent des incohérences entre les méthodes de mesure dans la vérification des hypothèses, l'ampleur moyenne à grande de l'effet observé dans les données favorisant une meilleure observance à une dose unique quotidienne souligne l'importance clinique potentielle de ces résultats.

Simultaneous Determination of Tacrolimus and Cyclosporine A in Whole Blood by Ultrafast LC-MS/MS.

Numerous methods for the measurement of tacrolimus and cyclosporine A involving traditional liquid chromatography tandem mass spectrometry (LC-MS/MS) have previously been described. The majority of these methods use solid-phase extraction, liquid-liquid extraction, or protein precipitation extraction with instrument run times greater than 15 s per sample. Continued demands in clinical labs for greater efficiency and throughput have put increased stress on traditional technologies such as high-performance liquid chromatography-ultraviolet detection (HPLC-UV) and traditional LC-MS/MS. As an improvement to the existing methods, we describe a sensitive ultrafast LC-MS/MS with run times of less than 15 s per sample.

Envarsus, a novelty for transplant nephrologists: Observational retrospective study. / Envarsus, una novedad para los nefrólogos del trasplante: estudio observacional retrospectivo.

The aim of this study was to evaluate the trough concentrations (Cptrough) and the tacrolimus dosage regimen after the conversion of Prograf or Advagraf to Envarsus (new pharmaceutical form with MeltDose technology that improves the absorption of fat-soluble drugs) in patients with stable renal transplantation, and their renal function. We selected stable renal transplant patients who were converted to Envarsus. Two periods were defined: Baseline and Conversion (Envarsus) and they were stratified according to the pharmaceutical form used in the Baseline period. Sixty-one patients were included (24 with Advagraf and 37 with Prograf), with an average age of 52years. The mean post-transplant time at the time of conversion to Envarsus was 76.3months and the mean follow-up in the Baseline and Conversion period was 10.1months and 11.6months, respectively. In the Prograf and Envarsus group, the Cptrough medians were 6.6 vs 6.4 ng/mL (P=.636), with a mean daily dose that decreased significantly from 3mg to 2mg (P<.001), respectively, maintaining the filtration rate. The median Cptrough values in the Advagraf and Envarsus groups were 5.7ng/mL and 6.3ng/mL (P=.07), with a median daily dose of 7mg and 4mg (P<.001), respectively, and the same renal function. In stable renal transplant patients, the conversion from Advagraf to Envarsus has allowed the dose of tacrolimus to be reduced by 42.9% and, in the case of Prograf, by 33.3%, maintaining similar Cptrough values, without renal function being altered.

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

INTRODUCTION: 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.

Comparison of the long-term efficacy and safety of generic tacrolimus, Tacrobell, with Prograf in liver transplant recipients.

INTRODUCTION: The purpose of this study was to compare the safety and efficacy of generic tacrolimus (Tacrobell [TCB]) and a reference tacrolimus (Prograf [PGF]) in liver transplant recipients. PATIENTS AND METHODS: We retrospectively analyzed 167 patients who used TCB or PGF between January 2009 and March 2016 for >1 year (TCB group, n=86; PGF group, n=81). To assess the efficacy and safety of TCB, we evaluated the relationship between drug dose and trough level, survival, rejection, infection, kidney function, and side effects. RESULTS: There was no difference in the preoperative demographics between the two groups. Moreover, there was no difference in the drug dose and trough level between the groups at 1 week after surgery. Coefficient of variation (CV) values were obtained at the drug trough level for each patient and no differences in CV values were identified within 1 year (p=0.587) and up to 5 years (p=0.824) in both groups. Rehospitalization (p=0.1) and total rejection (p=0.915) did not differ between the two groups, but the rejection severity, recorded as the rejection activity index value, was worse in the PGF group (p=0.039). No difference was found in the infection rate (p=0.818), and with regard to nephrotoxicity, there was no difference in the rate of patients with chronic kidney disease stage 3 and above during the follow-up period. No differences were found between the two groups in terms of drug side effects and adverse events. CONCLUSION: The generic tacrolimus, TCB, is a comparable alternative to the original tacrolimus, PGF, as a main immunosuppressive drug for liver transplantation.

Prograf produces more benefits for CYP3A5 low expression patients in early stage after kidney transplantation.

OBJECTIVE: This study is to analyze concentration changes of the prolonged-release and shorter-acting formulation of tacrolimus in patients with different CYP3A5 genotypes after kidney transplantation. METHODS: A single-factor retrospective analysis was performed in patients underwent allogeneic kidney transplantation with postoperative administration of Advagraf or Prograf in our hospital from May 2013 to June 2014. The CYP3A5 genotypes were determined, and tacrolimus trough concentrations in whole blood were measured within 28days after transplantation. The rates of acute rejection rate, chronic rejection and infection were recorded and compared after one year follow-up after surgery. RESULTS: The study included 106 patients administered Advagraf (45 cases) or Prograf (61 cases). The low expression genotype of CYP3A5 was detected in 40 (37.7%) patients. A higher dose of Advagraf was required to increase the tacrolimus trough concentrations within 21days after transplantation. Moreover, a higher dose for Advagraf than Prograf was required to increase the tacrolimus trough concentrations in low expression patients. In the low expression patients, Prograf more frequently achieved the target tacrolimus trough concentrations within seven days after transplantation (five days: 7.14% vs. 84%, P=0.001; seven days: 33.33% vs. 77.78%, P=0.001). The patient and kidney graft survival rates one year after transplantation both were 100%. The estimated glomerular filtration rate showed no significant difference between different CYP3A5 phenotypes or formulations of tacrolimus (P>0.05). However, the incidence of infections was higher in the Advagraf group in low expression patients (P<0.05). CONCLUSION: Tacrolimus of different formulations had different impact on patients with different CYP3A5 genotypes after kidney transplantation.

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

UNLABELLED: 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. RESULTS: 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. CONCLUSION: 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.

A single-centre comparison of the clinical outcomes at 6 months of renal transplant recipients administered Adoport® or Prograf® preparations of tacrolimus.

BACKGROUND: The use of generic formulations of immunosuppressive drugs in place of brand name drugs offers considerable cost savings. Brand name tacrolimus (Prograf®) came off patent in April 2008. However, published evidence supporting therapeutic equivalence of generic formulations of tacrolimus in solid organ transplantation is lacking. The South West Transplant Centre switched from administering Prograf® to a generic formulation (Adoport®) for de novo transplant recipients in November 2010. This study sought to compare the clinical outcomes of renal transplant recipients administered Prograf® with those receiving Adoport®. METHODS: Data regarding patient characteristics and clinical outcomes were collected retrospectively for all patients undergoing renal transplantation at the South West Transplant Centre between 8 November 2009 and 8 November 2011 to whom tacrolimus was prescribed. RESULTS: A total of 48 patients received Prograf® and 51 received Adoport®. At 6 months, no statistically significant differences were identified in the rates of patient survival, graft survival, acute allograft rejection, delayed graft function, calcineurin inhibitor toxicity or cytomegalovirus infection occurring within the two groups. CONCLUSIONS: This is the first study to compare the clinical outcomes of patients receiving Adoport® with those receiving brand name tacrolimus. We report comparable clinical outcomes at 6 months in patients receiving either Prograf® or Adoport® from the time of renal transplantation. These early outcome data therefore support the use of Adoport® in place of Prograf® as a potential cost-saving measure.