lunes, 25 de abril de 2016

Clinical Pharmacology Corner:FDA Approves ANTHIM (obiltoxaximab)

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FDA Approves ANTHIM (obiltoxaximab) injection for the Treatment and Prophylaxis of Inhalational Anthrax due to Bacillus anthracis
On March 18, 2016, the United States Food and Drug Administration (FDA) approved ANTHIM® (obiltoxaximab) injection under the “Animal Efficacy Rule” (21 CFR 601.90 “Approval of Biological Products when Human Efficacy Studies are not Ethical or Feasible”) for the treatment of adult and pediatric patients with inhalational anthrax due to Bacillus anthracis (B. anthracis) in combination with appropriate antibacterial drugs, and for prophylaxis of inhalational anthrax when alternative therapies are not available or are not appropriate. Adult and pediatric patients should be pre-medicated with diphenhydramine prior to ANTHIM administration. ANTHIM should be diluted in normal saline prior to administration and administered as a single dose intravenously over 90 minutes. Due to the risk of hypersensitivity and anaphylaxis, ANTHIM should be administered in monitored settings by personnel trained and equipped to manage anaphylaxis. ANTHIM infusion should be stopped immediately and patients treated appropriately if hypersensitivity or anaphylaxis occurs.
Recommended Dosage of ANTHIM in Adult and Pediatric Patients
Adult Patients:
  • Greater or equal to 40 kg: 16 mg/kg
  • Less than 40 kg: weight-based dosage as recommended for pediatric patients (see below)
Pediatric Patients:
  • Greater than 40 kg: 16 mg/kg
  • Greater than 15 kg to 40 kg: 24 mg/kg
  • Less than or equal to 15 kg: 32 mg/kg
Mechanism of Action (MOA), General Pharmacokinetics (PK) and Pharmacodynamics (PD) of ANTHIM
  • MOA: Obiltoxaximab is a deimmunized immunoglobulin G1 (IgG1) monoclonal antibody (mAb) that specifically binds the protective antigen (PA) of B. anthracis, thereby preventing its association with the anthrax toxin receptor on host cells.
  • Linearity: The PK of obiltoxaximab are linear over the dose range of 4 mg/kg (0.25 times the lowest recommended dose) to 16 mg/kg following single IV administration in healthy subjects.
  • Distribution: Mean obiltoxaximab steady-state volume of distribution was greater than plasma volume, suggesting some tissue distribution. 
  • Terminal Half-life: Approximately 15 to 23 days in healthy humans.
  • Excretion: Obiltoxaximab clearance was much smaller than the glomerular filtration rate indicating that there is virtually no renal clearance of obiltoxaximab.
  • Dose-Response: Based on observed and simulated data, healthy subjects and humans infected with B. anthracis achieve similar obiltoxaximab median Cmax and 2-fold greater median AUCinf following a single 16 mg/kg IV dose compared to exposures associated with efficacy in rabbits and monkeys in inhalational anthrax efficacy studies (see Efficacy and Safety). 
Drug Interaction Potential
Co-administration of 16 mg/kg ANTHIM intravenously with intravenous or oral ciprofloxacin in human subjects did not alter the PK of either ciprofloxacin or obiltoxaximab.
Use in Specific Populations
No dosage adjustment for ANTHIM is recommended based on gender (female versus male), race (non-Caucasian versus Caucasian), or age (elderly ≥65 years of age versus adults <65 age="" of="" p="" years="">
ANTHIM PK and safety have not been evaluated in children. A population PK approach was used to derive intravenous infusion dosing regimens that are predicted to provide pediatric patients with exposure comparable to the observed exposure in adults.
Efficacy and Safety
Because it is not feasible or ethical to conduct controlled clinical trials in humans with inhalational anthrax, the effectiveness of ANTHIM for the treatment and prophylaxis of inhalational anthrax is based on efficacy studies in animal models of inhalational anthrax (21 CFR 601, Subpart H). The efficacy of ANTHIM was based on survival rate on Day 28 after B. anthracis spore challenge in four monotherapy studies. A single 16 mg/kg IV dose of obiltoxaximab showed a significant survival benefit over placebo in both the cynomolgus macaque and New Zealand White (NZW) rabbit models of inhalational anthrax, with 28-day survival rates of 31 to 93% (ANTHIM) versus 0 to 6% (placebo). ANTHIM administered in combination with antibacterial drugs (levofloxacin, ciprofloxacin, and doxycycline) resulted in higher survival outcomes than antibacterial therapy alone. A 16 mg/kg IM dose, administered to cynomolgus macaques and NZW rabbits within 24 hours of exposure to B. anthracis spores was effective in preventing inhalational anthrax. Because obiltoxaximab exposures are lower with IM administration compared to IV administration at the same dose level, obiltoxaximab IV is expected to be effective for the prophylaxis of inhalational anthrax. The statistically significant survival benefit of ANTHIM compared to placebo in both animal models of inhalational anthrax indicates that ANTHIM is reasonably likely to produce clinical benefit in humans for the treatment and prophylaxis of inhalational anthrax.
The safety of obiltoxaximab was evaluated in over 400 healthy human volunteers. The main safety concerns for ANTHIM were hypersensitivity reactions which occurred in 10.6% of subjects and anaphylaxis which occurred in 0.9% of subjects. Hypersensitivity or anaphylaxis resulted in discontinuation of ANTHIM infusion in 2.5% of subjects (see introduction). Other common adverse events were headache, pruritus, cough, urticaria, and infections of the upper respiratory tract. Subjects who received pre-medication with diphenhydramine were less likely to experience adverse reactions with administration of ANTHIM compared to those who did not (42% vs. 58% respectively).

Full prescribing information is available at
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This burst was prepared by Office of Clinical Pharmacology, Office of Translational Sciences, CDER, FDA.

FDA/Center for Drug Evaluation and Research (CDER)
Office of Translational Sciences
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