Population pharmacokinetics and pharmacogenetics of once daily tacrolimus formulation in stable liver transplant recipients.

PURPOSE: The once daily formulation of tacrolimus is an important immunosuppressive drug. Interpatient variability in metabolism has been related to genetic variation in CYP3A4 and CYP3A5. However, in liver transplantation, both donor and recipient genotypes may affect pharmacokinetics. The primary objective of this study was to investigate the effect of CYP3A4*22 and CYP3A5*3 of both donor and recipient on once daily tacrolimus pharmacokinetics. The secondary objective was to develop a limited sampling model able to accurately predict exposure. METHODS: Stable liver transplant patients receiving once daily tacrolimus (N = 66) were included. Population pharmacokinetic analysis was performed with patients of whom DNA was available (N = 49), and demographic factors, CYP3A4*22 and CYP3A5*3, were tested as covariates. Moreover, a limited sampling model was developed using data of 66 patients. RESULTS: Pharmacokinetics was best described by a two-compartment model with delayed absorption. CYP3A5*1 carrying recipients engrafted with a CYP3A5*1 carrying liver had an average 1.7-fold higher clearance compared to non-carriers. CYP3A5*1 carrying recipients engrafted with a CYP3A5*1 non-carrying liver or vice versa showed an average 1.3-fold higher clearance compared with non-carriers. CYP3A4*22 was not significantly associated with once daily tacrolimus pharmacokinetics. Using 0, 2, and 3 h postdose as limited sampling model resulted in significantly improved prediction of tacrolimus exposure compared with trough concentration. CONCLUSIONS: Both donor and recipient CYP3A5 genotype significantly influences tacrolimus once daily pharmacokinetics. In contrast, CYP3A4*22 appears not suitable as biomarker. The developed limited sampling model can be used to accurately estimate tacrolimus once daily exposure.

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.

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.

Pharmacokinetics of Prolonged-Release Once-Daily Formulations of Tacrolimus in De Novo Kidney Transplant Recipients: A Randomized, Parallel-Group, Open-Label, Multicenter Study.

INTRODUCTION: Different prolonged-release formulations of tacrolimus are available. To date, the pharmacokinetic (PK) profile of LCP-tacrolimus (LCPT; Envarsus®) has not been compared with PR-Tac (Advagraf®) in de novo kidney transplant recipients. These profiles will guide clinical recommendations for the initiation and dose titration strategies of once-daily tacrolimus formulations. METHODS: This randomized, parallel-group, open-label, multicenter PK study randomized 75 de novo, adult, white kidney transplant recipients to LCPT 0.17 mg/kg/day (n = 37) or PR-Tac 0.20 mg/kg/day (n = 38) for 4 weeks. Dose adjustments were permitted to target a pre-defined therapeutic range based on measured trough blood concentrations. RESULTS: PK analysis (days 1, 3, 7 and 14) included 68 patients (LCPT, n = 33; PR-Tac, n = 35). Similar proportions of patients were within the pre-defined therapeutic tacrolimus trough blood concentration range, with < 12% in each group having below-target trough levels over the study period. LCPT demonstrated ~ 30% greater relative bioavailability [LCPT/PR-Tac adjusted geometric mean ratio: day 3, 1.32 (p = 0.007); day 7, 1.25 (p = 0.051); day 14, 1.43 (p = 0.002)] and ~ 30% lower peak-to-trough percentage fluctuation of blood concentration [LCPT/PR-Tac adjusted geometric mean ratio: day 3, 0.70 (p < 0.001); day 7, 0.68 (p < 0.001); day 14, 0.73 (p = 0.004)] in addition to longer time to maximum blood concentration (tmax), lower maximum concentration (Cmax) and a consistently lower daily dose (~ 40% dose reduction with LCPT vs. PR-Tac by day 28). Safety profiles were similar. CONCLUSION: In de novo kidney transplant recipients, prolonged-release formulations of tacrolimus can reach therapeutic concentrations in the immediate post-transplant period. LCPT has greater relative bioavailability and lower peak-to-trough fluctuation compared with PR-Tac. TRIAL REGISTRATION: Registered at ClinicalTrials.gov; study number NCT02500212. FUNDING: Chiesi Farmaceutici S.p.A.

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.

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.