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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]

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]

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]