Prolonged-Release vs Immediate-Release Tacrolimus Capsules in Black vs White Kidney Transplant Patients: A Post Hoc Analysis of Phase III Data.

BACKGROUND: Black kidney transplant patients experience inferior outcomes compared with other ethnicities. Because scrutiny is required when immunosuppressant drugs are used in such at-risk populations, we report the first large-scale clinical efficacy data assessing prolonged-release tacrolimus (PR-T) in black de novo kidney transplant patients. METHODS AND MATERIALS: We used logistic regression and proportionate hazards to compare a composite outcome measure (biopsy-proven acute rejection, graft loss, mortality, and loss to follow-up) in black and white patients in treatment groups longer than 24 weeks, from 3 large Phase III randomized controlled trials. Secondary endpoints included tacrolimus trough concentration, dose, and estimated glomerular filtration rate. RESULTS: The study included 2162 patients whose treatments belonged to two categories (immediate-release tacrolimus: 77 black patients, 721 white patients; and PR-T: 87 black patients, 1277 white patients). Despite demographic factors generally predictive of worse outcomes, efficacy failure among black patients who received PR-T was non-inferior to that among white patients who received either therapy. Compared with immediate-release tacrolimus, black patients who received PR-T achieved stable tacrolimus concentrations 2.5 times faster (21 vs 56 days, P = .04), and more achieved stable target concentrations (76.7% vs 69.3%). Treatment-emergent adverse events were consistent with those reported separately in pivotal trials. CONCLUSIONS: Overall, black patients who received PR-T achieved non-inferior outcomes compared to white patients, despite higher pretransplant risk among black patients. Moreover, PR-T improved the time to achieve, and the likelihood of reaching, stable therapeutic concentrations among black patients, suggesting that PR-T could improve the consistency of tacrolimus exposure in this patient population.

Renal Function in De Novo Liver Transplant Recipients Receiving Different Prolonged-Release Tacrolimus Regimens-The DIAMOND Study.

UNLABELLED: DIAMOND: multicenter, 24-week, randomized trial investigating the effect of different once-daily, prolonged-release tacrolimus dosing regimens on renal function after de novo liver transplantation. Arm 1: prolonged-release tacrolimus (initial dose 0.2mg/kg/day); Arm 2: prolonged-release tacrolimus (0.15-0.175mg/kg/day) plus basiliximab; Arm 3: prolonged-release tacrolimus (0.2mg/kg/day delayed until Day 5) plus basiliximab. All patients received MMF plus a bolus of corticosteroid (no maintenance steroids). PRIMARY ENDPOINT: eGFR (MDRD4) at Week 24. Secondary endpoints: composite efficacy failure, BCAR and AEs. Baseline characteristics were comparable. Tacrolimus trough levels were readily achieved posttransplant; initially lower in Arm 2 versus 1 with delayed initiation in Arm 3. eGFR (MDRD4) was higher in Arms 2 and 3 versus 1 (p = 0.001, p = 0.047). Kaplan-Meier estimates of composite efficacy failure-free survival were 72.0%, 77.6%, 73.9% in Arms 1-3. BCAR incidence was significantly lower in Arm 2 versus 1 and 3 (p = 0.016, p = 0.039). AEs were comparable. Prolonged-release tacrolimus (0.15-0.175mg/kg/day) immediately posttransplant plus basiliximab and MMF (without maintenance corticosteroids) was associated with lower tacrolimus exposure, and significantly reduced renal function impairment and BCAR incidence versus prolonged-release tacrolimus (0.2mg/kg/day) administered immediately posttransplant. Delayed higher-dose prolonged-release tacrolimus initiation significantly reduced renal function impairment compared with immediate posttransplant administration, but BCAR incidence was comparable.

Pharmacokinetics of micafungin in HIV positive patients with confirmed esophageal candidiasis.

Esophageal candidiasis (EC) is a common and serious complication in patients infected with the human immunodeficiency virus (HIV). Micafungin has been shown to have dose-related efficacy and to be well tolerated in patients with HIV and EC. This analysis of data from a randomized, double-blind study examined pharmacokinetic parameters of micafungin (dosed at 50, 100, and 150 mg/day) and its metabolites in a subset of patients with HIV and EC. Micafungin exhibited linear, predictable pharmacokinetics, similar to the previous observations in healthy control subjects. Micafungin peak plasma concentration and exposure were increased with dose, while half-life and clearance remained consistent with increasing dose. Plasma concentrations of the metabolites M-1, M-2, and M-5 remained low throughout the study (24 h exposure ≤14% relative to micafungin at end of therapy for each). No differences in micafungin pharmacokinetic parameters were observed according to the sex or race of the patients. The high systemic exposures associated with micafungin 100 and 150 mg/day relative to micafungin 50 mg/day were found to directly correlate with endoscopic clearance. These data provide evidence that the pharmacokinetics of micafungin underlie the dose-related efficacy in patients with HIV and EC.

Pharmacokinetics for once- versus twice-daily tacrolimus formulations in de novo kidney transplantation: a randomized, open-label trial.

Tacrolimus, a cornerstone immunosuppressant, is widely available as a twice-daily formulation (Tacrolimus BID). A once-daily prolonged-release formulation (Tacrolimus QD) has been developed that may improve adherence and impart long-lasting graft protection. This study compared the pharmacokinetics (PK) of tacrolimus in de novo kidney transplant patients treated with Tacrolimus QD or Tacrolimus BID. A 6-week, open-label, randomized comparative study was conducted in centers in Europe and Australia. Eligible patients received Tacrolimus QD or Tacrolimus BID. PK profiles were obtained following the first tacrolimus dose (day 1), and twice under steady-state conditions. As secondary objectives, efficacy and safety parameters were also evaluated. Sixty-six patients completed all PK profiles (34 Tacrolimus QD, 32 Tacrolimus BID). Mean AUC(0-24) of tacrolimus on day 1 was approximately 30% lower for Tacrolimus QD than Tacrolimus BID (232 and 361 ng.h/mL, respectively), but was comparable by day 4. There was a good correlation and a similar relationship between AUC(0-24) and C(min) for both formulations. Efficacy and safety data were also comparable over the 6-week period. Tacrolimus QD can be administered once daily in the morning on the basis of the same systemic exposure and therapeutic drug monitoring concept as Tacrolimus BID.

Skin and systemic pharmacokinetics of tacrolimus following topical application of tacrolimus ointment in adults with moderate to severe atopic dermatitis.

BACKGROUND: Systemic exposure to tacrolimus following topical application of tacrolimus ointment is minimal. There are, however, no data on the distribution of tacrolimus in the skin. OBJECTIVES: To assess the distribution of tacrolimus in the skin and the systemic pharmacokinetics of tacrolimus in adults with moderate to severe atopic dermatitis after first and repeated application of tacrolimus ointment. METHODS: We investigated skin distribution of topically applied tacrolimus and systemic pharmacokinetics of percutaneously absorbed tacrolimus in adults with atopic dermatitis after topical application of tacrolimus 0.1% ointment twice daily for 2 weeks. Tacrolimus concentrations were assessed in full-thickness skin biopsies and blood samples. RESULTS: Of 14 patients, 11 completed treatment and were analysed. Mean +/- SD tacrolimus concentrations in the skin at 24 h after first and last ointment applications were 94 +/- 20 and 595 +/- 98 ng cm(-3), respectively. At 168 h after stopping treatment, values were 97% lower than at 24 h after last application. Tacrolimus concentration decreased with increasing skin depth. Systemic tacrolimus exposure after ointment application was low and highly variable, with 31% of samples below the limit of quantification (0.025 ng mL(-1)) and 94% below 1 ng mL(-1). Blood concentrations at 24 h after the first and last ointment applications were 750 and 1800 times lower, respectively, than those in skin. Physicians' assessments showed that tacrolimus ointment was effective and well tolerated. CONCLUSIONS: Tacrolimus was primarily partitioned in the skin, with minimal systemic absorption after topical application, in patients with atopic dermatitis.

[Pharmacokinetics of tacrolimus following topical application of tacrolimus ointment in adult and paediatric patients with atopic dermatitis]. / Farmacocinética del tacrolimus tras la aplicación tópica de una pomada de tacrolimus en pacientes adultos y pediátricos con dermatitis atópica.

BACKGROUND: Safety concerns related to systemic immunosuppressive therapy have raised questions regarding systemic exposure to topically applied tacrolimus. OBJECTIVE: To summarise all currently available information on the pharmacokinetics of tacrolimus ointment and to compare it with the pharmacokinetics of systemic use of tacrolimus. RESULTS: Low and highly variable systemic exposure has been shown in pharmacokinetic studies of tacrolimus ointment performed in patients (adults and children) with moderate to severe atopic dermatitis. Patients with larger treatment areas tended to have higher exposure to the drug, but there was no evidence of systemic accumulation. Overall, 96, 92 and 97% of the blood samples assayed contained tacrolimus concentrations below 1 ng/ml, and 23, 17 and 20% of samples were below 0.025 ng/ml (the lower limit of quantification) in adults, children aged 6-12 and infants aged 3-24 months, respectively. CONCLUSION: Although tacrolimus applied topically is absorbed systemically, the overall exposure as measured by the area under the curve (AUC)0-24 is low and highly variable. The extent of systemic exposure is higher in patients with larger treatment areas, but even in patients with up to 75% of the body surface area treated, the systemic exposure is substantially lower than that measured in transplant patients. Systemic exposure to tacrolimus tends to decrease as the skin lesions heal and there is no evidence of systemic accumulation despite repeated applications of ointment. The tacrolimus ointment was efficacious and well-tolerated.

Physiochemical properties of generic formulations of tacrolimus in Mexico.

Tacrolimus is an important immunosuppressive agent used to prevent allograft rejection after transplantation. Tacrolimus has a narrow therapeutic index; therefore, it is essential that the physicochemical properties of generic formulations be identical to the brand-name formulation, Prograf. In this study, the physicochemical properties of generic tacrolimus formulations were compared with Prograf. The drug dissolution profiles of generic formulations of tacrolimus were different from that of Prograf. Tacrobell and T-Inmun exhibited faster dissolution than Prograf, and Tenacrine, Framebin, and Talgraf showed slower and incomplete drug dissolution, releasing 24% to 51% of tacrolimus within 2 hours. Generic formulations of tacrolimus demonstrated decreased solubility compared with Prograf. The solubility of Prograf was 35.7 microg/mL at 2 hours and 29.5 microg/mL at 24 hours. The solubility of Tenacrine, Framebin, and Talgraf at 2 hours was 5.5, 12.6, and 7.8 microg/mL, respectively, and the solubility decreased to 0.5, 2.3, and 2.1 microg/mL, respectively, at 24 hours. Whereas Prograf demonstrated content uniformity, the content of the generic tacrolimus formulations varied widely. The standard deviation of content for Tenacrine, Tacrobell, and T-Inmun were high at 29.3, 6.9, and 5.6, respectively. Furthermore, the mean percentage of labeled amount of T-Inmun was 84.2% with a relative standard deviation of 6.7% (minimum value; 72.7%; maximum value; 100.7%). These results indicate that generic formulations of tacrolimus tested in this study are not bioequivalent to Prograf, which suggests that their use may be of potential risk to transplant patients.

The disposition of 14C-labeled tacrolimus after intravenous and oral administration in healthy human subjects.

Tacrolimus is a macrolide lactone with potent immunosuppressive properties. It has been shown in clinical studies to prevent allograft rejection. The pharmacokinetics of tacrolimus in healthy subjects and transplant patients has been described in earlier studies using immunoassay methods; however, detailed information on the absorption, distribution, metabolism, and excretion of tacrolimus using a radiolabeled drug is lacking. The objective of the present study was to characterize the disposition of tacrolimus after single i.v. (0.01 mg/kg) and oral (0.05 mg/kg) administration of 14C-labeled drug in six healthy subjects. Tacrolimus was absorbed rapidly after oral dosing with a mean Cmax and Tmax of 42 ng/ml and 1 h, respectively. The oral bioavailability was about 20%. After i.v. and oral dosing, most of the administered dose was recovered in feces, suggesting that bile is the principal route of elimination. Urinary excretion accounted for less than 3% of total administered dose. In systemic circulation, unchanged parent compound accounted for nearly all the radioactivity; however, less than 0.5% of unchanged drug was detectable in feces and urine. The excretion of the metabolites was formation-rate-limited. The mean total body clearance at 37.5 ml/min was equivalent to about 3% of the liver blood flow. Renal clearance was less than 1% of the total body clearance. The mean elimination half-life was 44 h.

Pharmacokinetics of tacrolimus (FK506) in paediatric liver transplant recipients.

The pharmacokinetics of intravenous and oral tacrolimus was assessed in paediatric liver transplant patients at two centers in Europe. Sixteen patients, age 0.7 to 13 years, participated in the study; 12 patients were evaluable for intravenous pharmacokinetics, and 16 for oral. Intravenous tacrolimus was given as a continuous 24 h infusion (mean 0.037+/-0.013 mg/kg/day), and oral tacrolimus was given in 2 doses per day (mean 0.152+/-0.015 mg/kg). Whole blood samples for the intravenous pharmacokinetic profile were taken before initiation of the first infusion, 4, 8, 12 and 24 h post-infusion, and every 24 h thereafter until intravenous administration was discontinued. During the 12 h wash-out period between intravenous and oral administration, samples were taken every 3 h. Samples for the oral pharmacokinetic profile were taken immediately before the first oral dose and 0.5, 0.75, 1, 2, 2.5, 3, 4, 6, 8, 10 and 12 h post-administration. Non-compartmental procedures were used to characterise the pharmacokinetic parameters. Mean estimates for clearance and terminal half-life were 2.3+/-1.2 ml/min/kg and 11.5+/-3.8 h, respectively, following intravenous tacrolimus. The mean bioavailability of oral tacrolimus was 25+/-20%. A strong correlation was observed between AUC and trough whole blood levels of tacrolimus (r=0.90). The clearance was approximately 2-fold higher than that previously observed in adults; this could explain the higher dosage requirements in children.