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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. [ABSTRACT FROM AUTHOR]

Background and Objective: Given that a high intrapatient variability (IPV) of tacrolimus whole blood concentration increases the risk for a poor kidney transplant outcome, some experts advocate routine IPV monitoring for detection of high-risk patients. However, attempts to estimate the variance of tacrolimus trough concentrations (TTC) are limited by the need for patients to receive a fixed dose over time and/or the use of linear statistical models. A goal of this study is to overcome the current limitations through the novel application of statistical methodology generalizing the relationship between TTC and dose through the use of nonparametric functional regression modeling. Methods: With TTC as a response and dose as a covariate, the model employs an unknown bivariate function, allowing for the potentially complex, nonlinear relationship between the two parameters. A dose-adjusted variance of TTC is then derived based on standard functional principal component analysis (FPCA). To assess the model, it was compared against an FPCA-based model and linear mixed-effects models using prediction error, bias, and coverage probabilities for simulated data as well as phase III data from the Astellas new drug application studies for extended-release tacrolimus. Results: Our numerical investigation indicates that the new model better predicts dose-adjusted TTCs compared with the prediction of linear mixed effects models. Estimated coverage probabilities also indicate that the new model accurately accounts for the variance of TTC during the periods of large fluctuation in dose, whereas the linear mixed effects model consistently underestimates the coverage probabilities because of the inaccurate characterization of TTC fluctuation. Conclusion: This is the first known application of a functional regression model to assess complex relationships between TTC and dose in a real clinical setting. This new method has applicability in future clinical trials including real-world data sets due to flexibility of the nonparametric modeling approach. [ABSTRACT FROM AUTHOR]

Background: During antifungal prophylaxis, micafungin is generally infused IV once daily over 1 h. In practice, less-frequent dosing could improve the quality of life in patients requiring long-term treatment or prophylaxis. The feasibility of this approach was assessed using humanized doses of daily or infrequent micafungin regimens.Objectives: To evaluate the effectiveness of intermittent high-dose micafungin, simulating human exposure, for prophylaxis of invasive candidiasis in a rat model of chronic Candida albicans gastrointestinal colonization and systemic dissemination.Methods: Two weeks post-infection with an oral challenge of C. albicans, Sprague-Dawley rats were immunocompromised with a cytotoxic drug and a steroid. Rats received IV infusions of: daily vehicle control; daily subcutaneous micafungin (20 mg/kg SC); high-dose micafungin (20 mg/kg bolus SC + 80 mg/kg infusion/72 h, to simulate intermittent human dosing of 300 mg/72 h); or daily fluconazole by mouth (10 mg/kg PO). The effects of antifungal prophylaxis on faecal fungal burden and systemic C. albicans dissemination were evaluated.Results: A rat model of chronic C. albicans gastrointestinal colonization and systemic dissemination was established, characterized by a sustained microbiological burden over 29 days and fungal recovery from normally sterile tissues. Using this model, intermittent high-dose micafungin (delivered via iPrecio pumps) to simulate humanized doses of 300 mg/72 h was significantly more effective than vehicle control, as effective as once-daily micafungin and similar to daily fluconazole at reducing faecal burden and preventing systemic dissemination.Conclusions: These data indicate that intermittent high-dose micafungin can be as effective as daily therapy, supporting clinical assessment in high-risk patients requiring long-term antifungal prophylaxis. [ABSTRACT FROM AUTHOR]

Summary: The objectives of this study were to assess long‐term graft survival, patient survival, renal function, and acute rejections in de novo kidney transplant recipients, treated with once‐daily prolonged‐release tacrolimus‐based therapy. The study was a 5‐year non‐interventional prospective follow‐up of patients from the ADHERE study, a Phase IV 12‐month open‐label assessment of patients randomized to receive prolonged‐release tacrolimus in combination with mycophenolate mofetil (MMF) (Arm 1) or sirolimus (Arm 2). From 838 patients in the randomized study, 587 were included in the long‐term follow‐up, of whom 510 completed the study at year 5. At 1 year post‐transplant, graft and patient survival rates were 93.0% and 97.8%, respectively, and at 5 years were 84.0% and 90.8%, respectively. Cox proportional hazards analysis showed no association between graft loss, initial randomized treatment arm, donor age, donor type, or sex. The 5‐year acute rejection‐free survival rate was 77.4%, and biopsy‐confirmed acute rejection‐free survival rate was 86.0%. Renal function remained stable over the follow‐up period: mean ± SD eGFR 4‐variable modification diet in renal disease formula (MDRD4) was 52.3 ± 21.6 ml/min/1.73 m2 at 6 months and 52.5 ± 23.0 ml/min/1.73 m2 at 5 years post‐transplant. These findings support the role of long‐term once‐daily prolonged‐release tacrolimus‐based immunosuppression, in combination with sirolimus or MMF, for renal transplant recipients in routine clinical practice. [ABSTRACT FROM AUTHOR]

Tacrolimus has significantly improved outcomes for kidney transplant patients and remains the cornerstone of immunosuppressive therapy. While improvements in short-term outcomes in transplantation have been achieved in recent years, maintaining long-term graft survival remains a challenge in kidney transplantation. Minimizing risk factors for poor long-term kidney graft function and survival, and modifying tacrolimus regimens in the early and maintenance phases post-transplantation are essential to maintain long-term kidney transplant outcomes. Tacrolimus has a narrow therapeutic window, resulting in a tightly defined range of optimal drug exposure. Underimmunosuppression is associated with long-term risks, such as the development of donor-specific antibodies and antibody-mediated rejection, with a high possibility of a decline in kidney function and progression to graft failure. Conversely, prolonged overimmunosuppression carries a risk of drug-related adverse events. This review provides an overview of the differences in the formulation, delivery, and pharmacokinetic profiles between immediate- and prolonged-release tacrolimus and evaluates the effect of prolonged-release tacrolimus on the risk factors for poor outcomes in kidney transplantation. Recent evidence is used to provide guidance on target tacrolimus trough levels in the early and maintenance phases post-transplantation, with a view to improving long-term kidney graft function. • Tacrolimus is the mainstay of immunosuppression therapy post-kidney transplantation. • Long-term outcomes for kidney transplant recipients remain challenging. • Graft loss risk factors can be managed by immunosuppressive regimen and adherence. • Nonadherence and intrapatient variability in tacrolimus levels predict graft loss. • Prolonged-release tacrolimus could improve long-term kidney transplant outcomes. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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 Ctrough 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 AUCtau after first dose of tacrolimus was 211, 97, and 224 hour*ng/mL in liver, kidney, and heart transplant recipients, respectively; corresponding mean AUCtau at steady state was 195, 208, and 165 hour*ng/mL. Ctrough and AUCtau 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 Ctrough is a reliable marker for TDM in pediatric transplant recipients treated with tacrolimus granules, consistent with TDM for other tacrolimus formulations. [ABSTRACT FROM AUTHOR]

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 ( AUC0-24) was higher with prolonged-release versus immediate-release tacrolimus. Dose-normalized AUC0-24 (normalized to 0.1 mg/kg/day) showed generally lower exposure with prolonged-release tacrolimus versus immediate-release tacrolimus. There was good correlation between AUC0-24 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). [ABSTRACT FROM AUTHOR]

Background Tacrolimus ointment is effective for treatment of moderate to severe atopic dermatitis (AD) in children aged ≥2 years ( Br J Dermatol, 2004; 150: 554). Here, efficacy and tolerability of tacrolimus 0.03% ointment were evaluated in 50 infants aged <2 years at start of treatment. Methods Infants with AD previously enrolled in a tacrolimus ointment pharmacokinetics trial were eligible for a 24-month open-label phase II study. Tacrolimus 0.03% ointment was applied to affected areas until clearance. In cases of exacerbation or clinical worsening, patients restarted treatment. Results Mean ± SD Eczema Area and Severity Index (EASI) score improved, from 11.2 ± 10.5 baseline to 2.6 ± 4.1 at endpoint (24 months); mean affected body surface area decreased from 25.2 ± 21.1% to 5.1 ± 9.0%, with improvement on all items of the Physicians' Assessment of Individual Signs. The Physicians' Global Evaluation of Clinical Response showed a result of 'cleared'/'excellent' for 63.3% of patients; 85.7% of parents/guardians assessed symptoms as 'much better.' Treatment was well tolerated, with common, nonserious respiratory infections and gastroenteritis the most frequently reported adverse events. The most common application-site events were infections and pruritus. Over 98% of blood samples showed tacrolimus concentrations <1.0 ng/ml; >40% showed concentrations below the lower limit of quantification (0.0250 ng/ml). Conclusions Over a period of two years, tacrolimus 0.03% ointment was associated with substantial clinical improvement of AD in infants aged <2 years. Treatment tolerability was similar to that seen in older children. [ABSTRACT FROM AUTHOR]

Background: A prolonged-release formulation of tacrolimus for once-daily administration (tacrolimus QD) has been developed. This phase II, open-label, multicenter, prospective single-arm study compared the pharmacokinetics (PK) of tacrolimus in stable heart transplant patients before and after conversion from twice-daily tacrolimus (tacrolimus BID) to tacrolimus QD. Methods: Heart transplant recipients (≥6 months after transplant), previously maintained on tacrolimus BID–based therapy, received tacrolimus BID from Days 1 to 7 and were converted on a 1:1 (mg/mg) basis to tacrolimus QD. Five 24-hour PK profiles were collected (Days 1, 7, 8, 14, 21). Safety parameters were also evaluated. Results: Of 85 patients, 45 (50.6%) completed all 5 evaluable PK profiles. Steady-state tacrolimus area under the curve, 0 to 24 hours (AUC0–24) and minimum concentration (Cmin) were comparable for both formulations, with treatment ratio means of 90.5% (90% confidence intervals [CI], 86.4%–94.6%) and 87.4% (95% CI, 82.9%–92.0%), respectively (acceptance interval, 80%–125%). There was good correlation between AUC0–24 and Cmin for tacrolimus QD (r = 0.94) and BID (r = 0.91). The relationship between these 2 parameters was also similar. Conclusions: This study provides evidence for successful conversion from tacrolimus BID to QD on a 1:1 (mg/mg) total daily dose basis. Approximately one-third of patients may require dose adjustments. Both formulations were well tolerated, with stable renal function during the study. Adverse events were reported by approximately one-tenth of patients receiving tacrolimus BID and a quarter of those who received QD. [ABSTRACT FROM AUTHOR]

Background In adults and children aged > 2 years, systemic absorption of tacrolimus from tacrolimus ointment is very low. In this study, the pharmacokinetics of tacrolimus 0.03% ointment were investigated in infants aged 3–24 months. Methods The pharmacokinetics of tacrolimus after first and repeated topical application of tacrolimus 0.03% ointment were evaluated in 53 infants (age, 3–24 month) with atopic dermatitis requiring treatment with mid-potency topical corticosteroids. Patients were grouped according to percentage of body surface area affected (Group 1: 5–20%; Group 2: > 20–40%; Group 3: > 40%). After stratification, patients were randomized (double-blind) to receive once-daily or twice-daily tacrolimus 0.03% ointment. Results Blood samples taken on days 1 and 14 (first and last application) showed minimal systemic tacrolimus exposure. Overall, 97% of blood samples assayed contained tacrolimus concentrations < 1 ng/ml, and 20% were below the lower limit of quantification (0.025 ng/ml). Systemic tacrolimus exposure was variable, but tended to increase as the treated body surface area increased. Mean apparent half-life of tacrolimus was 80 ± 35 h (range: 25–175 h). Most patients experienced substantial clinical improvement in their atopic dermatitis. There were no clinically significant changes in laboratory values, and the most frequently reported adverse events were minor infections and local skin irritations. Conclusions Tacrolimus 0.03% ointment in infants is associated with very low systemic exposure to tacrolimus. Treatment was well tolerated and led to considerable clinical improvement. [ABSTRACT FROM AUTHOR]

The systemic exposure to tacrolimus after first and repeated application of 0.1% tacrolimus ointment was investigated in 32 adults with moderate to severe atopic dermatitis. Patients were allocated to treatment groups according to the size of the affected area to be treated: Group 1⩽3000 cm2 (N=11); Group 2>3000 cm2⩽6000 cm2 (N=12); Group 3>6000 cm2⩽10,000 cm2 (N=9). Ointment was applied twice daily for 13 d and once daily on Day 14; the size of application area remained the same irrespective of healing. Blood samples were collected on Days 1 (first application), 4, and 14 (last application) and analyzed by a validated HPLC-MS/MS method. Systemic exposure to tacrolimus was generally low with 96% of blood samples assayed containing concentrations below 1 ng per mL and 23% of samples below the lower limit of quantification (0.025 ng per mL). Peak concentrations after first ointment application were ⩽2.8 ng per mL, and the mean area under the concentration–time curve between 0 and 12 h using the trapezoidal rule (AUC0–12) values were 1.1, 1.6, and 4.8 ng h per mL for Groups 1, 2, and 3, respectively. The corresponding mean values on Day 14 were similar indicating negligible systemic accumulation of tacrolimus after repeated ointment applications. Both the rate and extent of topical absorption decreased as the skin lesions healed. [ABSTRACT FROM AUTHOR]

The pharmacokinetics of tacrolimus after first and repeated application of 0.1% tacrolimus ointment were evaluated in 39 children, aged 6–12 y, with moderate to severe atopic dermatitis. The patients were grouped according to the size of the affected body surface area to be treated: Group 1⩽1500 cm2; Group 2>1500 cm2⩽3000 cm2; Group 3>3000 cm2⩽5000 cm2. Serial blood samples to calculate pharmacokinetic parameters taken on Day 1 (first ointment application) and Day 14 (last application) showed minimal systemic exposure to tacrolimus. Overall, 92% of the blood samples assayed contained tacrolimus concentrations below 1 ng per mL and 17% of samples were below 0.025 ng per mL, the lower limit of quantification. Systemic exposure to tacrolimus varied between patients and tended to increase proportionally as the size of the treated body surface area increased. Absorption decreased with time as the skin lesions healed and there was no evidence of systemic accumulation. The mean apparent half-life of tacrolimus (t1/2, z) was 66±27 h (range 19–125 h). Most patients experienced substantial clinical improvement in their atopic dermatitis. There were no clinically relevant changes in laboratory values, and the most frequently reported adverse event was skin burning, which resolved quickly as the skin condition improved. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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 (AUC24); secondary end‐points were maximum concentration Cmaxand concentration at 24 hours C24. 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 AUC24, max, and C24, and for kidney and liver recipients for AUC24 (LSM ratio, kidney 91.8%; liver 104.1%) and C24 (kidney 90.5%; liver 89.9%). Linear relationship was similar between AUC24 and C24, 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. [ABSTRACT FROM AUTHOR]

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 AUC24. Secondary end points included tacrolimus C24 and Cmax. 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, AUC24 and Cmax 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 AUC24; 66.3%, 82.2%, 90.9% for C24; and 77.3%, 120.3%, 92.2% for Cmax. AUC24 90% CI within predefined similarity interval on Day 28; other 90% CIs fell outside. Linear relationship was similar between AUC24 and C24, and between tacrolimus formulations, suggesting that the same therapeutic drug monitoring method can be used with both formulations in de novo pediatric allograft recipients. [ABSTRACT FROM AUTHOR]