The Association of Tacrolimus Formulation Switching with Trough Concentration Variability: A Retrospective Cohort Study of Tacrolimus Use Post-Kidney Transplantation Based on National Drug Code (NDC) Numbers.

INTRODUCTION: It was hypothesized that patients experiencing at least one tacrolimus formulation switch may require more frequent therapeutic drug monitoring, subsequent dose adjustments, and a potential for untoward clinical outcomes than patients who remain on a single formulation. METHODS: Eligible patients were adult kidney transplant recipients with stable renal function at month 3 post-transplant and no evidence of acute rejection, receiving an oral, tacrolimus-based regimen. Patients were categorized into two groups (fixed or variable formulation) using the US National Drug Code (NDC) on the basis of tacrolimus formulation usage over the 12-month period. RESULTS: A total of 305 patients were enrolled from four US transplant centers; 44 (14.4%) received multiple formulations and 261 (85.6%) received a single formulation. Mean number of tacrolimus dose adjustments and mean cumulative milligram dose change were not statistically different between the two groups. Mean trough-to-dose ratio, frequency of trough level measurements, and mean number of excursions above 120% or below 80% of the patient's mean trough concentration were significantly higher in the variable compared to the fixed formulation group. CONCLUSION: A variable tacrolimus formulation regimen was associated with a higher frequency of trough level measurements and a greater number of excursions in trough levels compared with continuing on a fixed formulation regimen of tacrolimus in this retrospective chart review study. FUNDING: Astellas Pharma Global Development, Inc. Plain language summary available for this article.

Micafungin (FK463), alone or in combination with other systemic antifungal agents, for the treatment of acute invasive aspergillosis.

BACKGROUND: Micafungin (FK463) is a new lipopeptide compound (echinocandin) with activity against Aspergillus and Candida species. This study evaluated the safety and efficacy of micafungin in patients with proven or probable invasive aspergillosis (IA). METHODS: A multinational, non-comparative study was conducted to examine proven or probable (pulmonary only) Aspergillus species infection in a wide variety of patient populations. The study employed an open-label design utilizing micafungin alone or in combination with another systemic antifungal agent. Criteria for IA and therapeutic responses were judged by an independent panel. RESULTS: Of the 331 patients enrolled, only 225 met diagnostic criteria for IA as determined by the independent panel and received at least one dose of micafungin. Patients included 98/225 who had undergone hematopoietic stem cell transplantation (HSCT) (88/98 allogeneic), 48 with graft versus host disease (GVHD), and 83/225 who had received chemotherapy for hematologic malignancy. A favorable response rate at the end of therapy was seen in 35.6% (80/225) of patients. Of those only treated with micafungin, favorable responses were seen in 6/12 (50%) of the primary and 9/22 (40.9%) of the salvage therapy group, with corresponding numbers in the combination treatment groups of 5/17 (29.4%) and 60/174 (34.5%) of the primary and salvage treatment groups, respectively. Of the 326 micafungin-treated patients, 183 (56.1%) died during therapy or in the 6-week follow-up phase; 107 (58.5%) deaths were attributable to IA. CONCLUSIONS: Micafungin as primary or salvage therapy proved efficacious and safe in high-risk patients with IA, although patient numbers are small in the micafungin-only groups.

Safety, tolerability, and pharmacokinetics of Micafungin (FK463) in febrile neutropenic pediatric patients.

Micafungin (FK463) is a new parenteral echinocandin. A multicenter, phase I, open-label, sequential-group dose escalation study was conducted to assess the safety, tolerability, and pharmacokinetics of micafungin in neutropenic pediatric patients. A total of 77 patients stratified by age (2 to 12 and 13 to 17 years) received micafungin. Therapy was initiated at 0.5 mg/kg per day and escalated to higher dose levels of 1.0, 1.5, 2.0, 3.0, and 4.0 mg/kg per day. Micafungin was administered within 24 h of initiating broad-spectrum antibacterial antibiotics for the new onset of fever and neutropenia. The most common overall adverse events in the study population were diarrhea (19.5%), epistaxis (18.2%), abdominal pain (16.9%), and headache (16.9%). Nine patients (12%) experienced adverse events considered by the investigator to be possibly related to the study drug. The most common related events were diarrhea, vomiting, and headache, all occurring in two patients each. There was no evidence of a dose-limiting toxicity as defined within the prespecified criteria of this clinical protocol. There was one death during the study due to septic shock. The pharmacokinetic profiles for micafungin over the 0.5- to 4.0-mg/kg dose range demonstrated dose linearity. Clearance, volume of distribution, and half-life remained relatively constant over the dose range and did not change with repeated administration. The overall plasma pharmacokinetic profile was similar to that observed in adults. However, there was an inverse relation between age and clearance. For patients 2 to 8 years old, clearance was approximately 1.35 times that of patients >/=9 years of age. In summary, micafungin over a dosage range between 0.5 and 4.0 mg/kg/day in 77 febrile neutropenic pediatric patients displayed linear pharmacokinetics and increased clearance as a function of decreasing age.