Pharmacokinetics and pharmacodynamics of a novel depot formulation of abarelix, a gonadotropin-releasing hormone (GnRH) antagonist, in healthy men ages 50 to 75.

This study evaluated the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of a novel depot formulation of abarelix, a new gonadotropin-releasing hormone (GnRH) antagonist. This was an open-label, sequential two-phase study in healthy male subjects ages 50 to 75. Subjects received a single intramuscular (IM) dose of 15 microg/kg abarelix injectable solution, followed by a 21-day washout period and a subsequent intramuscular dose of 100 mg abarelix depot. The PK and the hormonal suppression effects of abarelix were evaluated based on testosterone (T), dihydrotestosterone (DHT), follicle-stimulating hormone (FSH), and luteinizing hormone (LH) levels. Abarelix provides immediate competitive blocking of the GnRH receptors on pituitary gonadotropes without causing release of gonadotropins, and these effects are reversible. The mean IC(50)s of abarelix for T, DHT, FSH, and LH were 2.08, 3.42, 6.43, 4.25 ng/mL, respectively. The mean relative bioavailability of the depot formulation in reference to the injectable solution was 0.52. The mean t(max) and terminal t(1/2) for abarelix after administration of abarelix injectable solution and abarelix depot injection were 1 hour and 3 days and 0.22 days (5.3 h) and 13.2 days, respectively. The novel abarelix depot formulation used in this study significantly improved the duration of abarelix delivery and pharmacological activities compared to the injectable formulation, without causing any safety issues.

Multicenter, double-blind, placebo-controlled study of the use of filgrastim in patients hospitalized with pneumonia and severe sepsis.

OBJECTIVE: To determine the safety and efficacy of filgrastim (r-metHuG-CSF) in combination with intravenous antibiotics to reduce the rate of mortality in patients with pneumonia and sepsis. DESIGN: This study was multicenter, double-blind, and randomized. SETTING: Intensive care units PATIENTS Adult patients with bacterial pneumonia, either acquired or nosocomial, as confirmed by chest radiograph and positive culture or Gram-negative stain, and severe sepsis, defined as sepsis-induced hypotension or organ dysfunction. INTERVENTIONS: Standard antibiotic therapy with or without filgrastim (300 microg/day) or placebo administered as a 30-min intravenous infusion. The study drug was started within 24 hrs of enrollment and was continued for 5 days or until the white blood cell count reached >75.0 x 10(9) cells/L. MEASUREMENTS AND MAIN RESULTS: The primary end point was the occurrence of mortality through day 29; secondary end points included occurrence of subsequent organ dysfunction, time to discharge from intensive care unit, number of days on mechanical ventilatory support, and time to death. Study-related observations were recorded through day 10 and included vital signs, onset of organ dysfunction, clinical laboratory variables, and adverse events. Filgrastim increased the white blood cell count to a median peak of 31.7 x 10(9) cells/L from a baseline of 12.3 x 10(9) cells/L. The two groups were well matched and did not differ significantly with regard to severe adverse events, time to death, occurrence of end-organ dysfunction, days of intensive care unit hospitalization, or days on mechanical ventilatory support. Mortality was low in both treatment groups; the mortality rate in patients with adult respiratory distress syndrome was similar between the two groups. CONCLUSIONS: The addition of filgrastim to the antibiotic and supportive care treatment of patients with pneumonia complicated by severe sepsis appeared to be safe, but not efficacious in reducing mortality rates or complications from this infection.

A phase 3, multicenter, open label, randomized study of abarelix versus leuprolide plus daily antiandrogen in men with prostate cancer.

PURPOSE: We compared the endocrinological and biochemical efficacy of abarelix depot, a gonadotropin-releasing hormone antagonist, with that of a widely used combination of luteinizing hormone releasing hormone agonist and a nonsteroidal antiandrogen. MATERIALS AND METHODS: A total of 255 patients were randomized to receive open label 100 mg. abarelix depot or 7.5 mg. leuprolide acetate intramuscularly injection on days 1, 29, 57, 85, 113 and 141 for 24 weeks. Patients in the abarelix group received an additional injection on day 15 and those in the leuprolide acetate group received 50 mg. bicalutamide daily. Patients could continue treatment with study drug for an additional 28 weeks. The efficacy end points were the comparative rates of avoidance of testosterone surge (greater than 10% increase) within 7 days of the first injection and the rapidity of achieving reduction of serum testosterone to castrate levels (50 ng./dl. or less) on day 8. Patients were monitored for adverse events and laboratory abnormalities. RESULTS: Abarelix was more effective in avoidance of testosterone surge (p <0.001) and the rapidity of reduction of testosterone to castrate levels on day 8 (p <0.001) than combination therapy. No significant difference was seen between the groups in the initial rate of decline of serum prostate specific antigen or the ability to achieve and maintain castrate levels of testosterone. No unusual or unexpected adverse events were reported. CONCLUSIONS: Abarelix as monotherapy achieves medical castration significantly more rapidly than combination therapy and avoids the testosterone surge characteristic of agonist therapy. Both treatments were equally effective in reducing serum prostate specific antigen, and achieving and maintaining castrate levels of testosterone.