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Background and Aims: This multicenter trial compared immediate-release tacrolimus (IR-T) vs prolonged-release tacrolimus (PR-T) in de novo kidney, liver, and heart transplant recipients aged <16 years. Each formulation had similar pharmacokinetic (PK) profiles. Follow-up efficacy and safety results are reported herein., Materials and Methods: Patients, randomized 1:1, received once-daily, PR-T or twice-daily, IR-T within 4 days of surgery. After a 4-week PK assessment, patients continued randomized treatment for 48 additional weeks. At Year 1, efficacy assessments included the number of clinical acute rejections, biopsy-confirmed acute rejection (BCAR) episodes (including severity), patient and graft survival, and efficacy failure (composite of death, graft loss, BCAR, or unknown outcome). Adverse events were assessed throughout., Results: The study included 44 children. At Year 1, mean ± standard deviation tacrolimus trough levels were 6.6 ± 2.2 and 5.4 ± 1.6 ng/mL, and there were 2 and 7 acute rejection episodes in the PR-T and IR-T groups, respectively. No cases of graft loss or death were reported during the study. The overall efficacy failure rate was 18.2% (PR-T n = 1; IR-T n = 7)., Conclusions: In pediatric de novo solid organ recipients, the low incidence of BCAR and low efficacy failure rate suggest that PR-T-based immunosuppression is effective and well tolerated to 1-year post-transplantation., (© 2019 The Authors. Clinical Transplantation published by John Wiley & Sons Ltd.)

This study was a Phase II, open-label, multicenter, single-arm, cross-over study comparing the pharmacokinetics (PK) of tacrolimus in stable pediatric kidney, liver, or heart allograft recipients converted from immediate-release tacrolimus (IR-T) to prolonged-release tacrolimus (PR-T). In Days -30 to -1 of screening period, patients received their IR-T-based regimen; during Days 1-7, patients received study IR-T (same dose as screening). On Day 7, the first 24-hours PK profile was taken; patients were then converted to PR-T (1 mg:1 mg), with a second 24-hours PK profile taken on Day 14. The primary end-point was tacrolimus area under the blood concentration-time curve over 24 hours (AUC 24 ); secondary end-points were maximum concentration C max and concentration at 24 hours C 24 . The predefined similarity interval for confidence intervals (CIs) of least squares mean (LSM) ratios was 80%-125%. The PK analysis set comprised 74 pediatric transplant recipients (kidney, n = 45; liver, n = 28; heart, n = 1). PR-T:IR-T LSM ratio (90% CI) was similar overall for AUC 24 , max , and C 24 , and for kidney and liver recipients for AUC 24 (LSM ratio, kidney 91.8%; liver 104.1%) and C 24 (kidney 90.5%; liver 89.9%). Linear relationship was similar between AUC 24 and C 24 , and between PR-T and IR-T (rho 0.89 and 0.84, respectively), suggesting that stable pediatric transplant recipients can be converted from IR-T to PR-T at the same total daily dose, using the same therapeutic drug monitoring method., (© 2019 The Authors. Pediatric Transplantation published by Wiley Periodicals, Inc.)

Tacrolimus granules were developed for patients who are unable to swallow capsules. Therapeutic drug monitoring (TDM) is required to optimize efficacy and safety, which is based on C trough for tacrolimus capsules. Pharmacokinetic (PK) data for tacrolimus granules are required to establish the basis for TDM in those who are unable to swallow capsules. In this phase IV study (NCT01371331) of children undergoing liver, kidney, or heart transplantation, patients received tacrolimus granules 0.15 mg/kg twice daily; first dose was administered within 24 hours of reperfusion. PK analysis samples were collected after reperfusion, after first dose of tacrolimus (Day 1), and at steady state (Day 7; >4 days stable dose). Of the 52 transplant recipients enrolled, 38 had two evaluable PK profiles. Mean AUC tau after first dose of tacrolimus was 211, 97, and 224 hour*ng/mL in liver, kidney, and heart transplant recipients, respectively; corresponding mean AUC tau at steady state was 195, 208, and 165 hour*ng/mL. C trough and AUC tau were positively correlated after first dose of tacrolimus and at steady state (Pearson's coefficients: r = 0.81 and r = 0.87, respectively). This study demonstrated that C trough is a reliable marker for TDM in pediatric transplant recipients treated with tacrolimus granules, consistent with TDM for other tacrolimus formulations., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Phase 2, parallel-group, multicenter, open-label, 4-week study, comparing PK of PR-T vs IR-T in de novo pediatric patients undergoing primary kidney, liver, or heart transplantation. Patients randomized 1:1 to receive once daily, PR-T-, or twice-daily, IR-T-based regimens; dose adjustments permitted after Day 1. Twenty-four-hour PK profiles collected on Days 1, 7, and 28. Primary endpoint: tacrolimus AUC 24 . Secondary end points included tacrolimus C 24 and C max . Endpoints compared between PR-T and IR-T on Days 1, 7, and 28. Predefined similarity interval for CIs of LSM ratios: 80%-125%. PK analysis set comprised 33 patients (PR-T, n = 15; IR-T, n = 18). Overall, AUC 24 and C max were lower on Day 1 vs 7 and 28. Geometric LSM ratios of PR-T:IR-T on Days 1, 7, and 28 were 66.3%, 92.5%, 99.9%, respectively, for AUC 24 ; 66.3%, 82.2%, 90.9% for C 24 ; and 77.3%, 120.3%, 92.2% for C max . AUC 24 90% CI within predefined similarity interval on Day 28; other 90% CIs fell outside. Linear relationship was similar between AUC 24 and C 24 , and between tacrolimus formulations, suggesting that the same therapeutic drug monitoring method can be used with both formulations in de novo pediatric allograft recipients., (© 2018 The Authors. Pediatric Transplantation published by Wiley Periodicals, Inc.)

Background: With the same dose of tacrolimus, lower systemic exposure on the first day of dosing has been reported for prolonged-release tacrolimus compared with immediate-release tacrolimus, prompting investigation of differing initial doses., Methods: This substudy of a double-blind, randomized, phase III trial in de novo liver transplant recipients compared the pharmacokinetics of once-daily prolonged-release tacrolimus (initial dose: 0.2 mg/kg/day) versus twice-daily immediate-release tacrolimus (initial dose: 0.1 mg/kg/day) during the first 2 weeks post-transplant., Results: Pharmacokinetic data were analyzed from patients receiving prolonged-release tacrolimus (n=13) and immediate-release tacrolimus (n=12). Mean systemic exposure (AUC 0-24 ) was higher with prolonged-release versus immediate-release tacrolimus. Dose-normalized AUC 0-24 (normalized to 0.1 mg/kg/day) showed generally lower exposure with prolonged-release tacrolimus versus immediate-release tacrolimus. There was good correlation between AUC 0-24 and concentration at 24 hours after the morning dose (r=.96 and r=.86, respectively), and the slope of the line of best fit was similar for both formulations., Conclusions: Doubling the initial starting dose of prolonged-release tacrolimus compared with immediate-release tacrolimus overcompensated for lower exposure on Day 1. A 50% higher starting dose of prolonged-release tacrolimus than immediate-release tacrolimus may be required for similar systemic exposure. However, doses of both formulations can be optimized using the same trough-level monitoring system. (ClinicalTrials.gov number: NCT00189826)., (© 2017 The Authors. Clinical Transplantation Published by John Wiley & Sons Ltd.)

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., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)