Bezlotoxumab is a human monoclonal antitoxin antibody that binds with high affinity to C. difficile toxin B and neutralizes its activity. Bezlotoxumab prevents CDI recurrence by providing passive immunity against toxin produced by the outgrowth of persistent or newly-acquired C. difficile spores.
Activity in vitro and in vivo: The toxin B epitope to which bezlotoxumab binds is conserved, though not identical, across all known toxin sequences.
Bezlotoxumab is dosed via the IV route and therefore is immediately and completely bioavailable. After a single IV dose of 10 mg/kg bezlotoxumab, mean AUC(0-∞) and Cmax were 53,000 mcg.h/mL and 185 mcg/mL, respectively, in patients with CDI. Bezlotoxumab exposures in healthy subjects increased in an approximately dose proportional manner across the 0.3 to 20 mg/kg dose range.
Bezlotoxumab has limited extravascular distribution. The mean volume of distribution of bezlotoxumab was 7.33 L (CV: 16%).
Bezlotoxumab is catabolized through protein degradation processes; metabolism does not contribute to its clearance.
Bezlotoxumab is eliminated from the body primarily by protein degradation. The mean clearance of bezlotoxumab was 0.317 L/day (CV: 41%) and the terminal half-life (t1⁄2) was approximately 19 days (28%).
The effects of various covariates on the pharmacokinetics of bezlotoxumab were assessed in a population pharmacokinetic analysis. The clearance of bezlotoxumab increased with increasing body weight; the resulting exposure differences are adequately addressed by the administration of a weight-based dose.
The following factors had no clinically meaningful effect on the exposure of bezlotoxumab and no dose adjustment is required: age (range 18 to 100 years), gender, race, ethnicity, renal impairment, hepatic impairment, and presence of co-morbid conditions.
The effect of renal impairment on the pharmacokinetics of bezlotoxumab was evaluated in patients with mild (eGFR 60 to <90 mL/min/1.73 m²), moderate (eGFR 30 to <60 mL/min/1.73 m²), or severe (eGFR 15 to <30 mL/min/1.73 m²) renal impairment, or with end stage renal disease (eGFR <15 mL/min/1.73 m²), as compared to patients demonstrating normal (eGFR ≥90 mL/min/1.73 m²) renal function. No clinically meaningful differences in the exposure of bezlotoxumab were found between patients with renal impairment and patients with normal renal function.
The effect of hepatic impairment on the pharmacokinetics of bezlotoxumab was evaluated in patients with hepatic impairment (defined as having two or more of the following: 1 albumin ≤3.1 g/dL; 2 ALT ≥2X ULN; 3 total bilirubin ≥1.3X ULN; or 4 mild, moderate or severe liver disease as reported by the Charlson Co-morbidity Index), as compared to patients with normal hepatic function. No clinically meaningful differences in the exposure of bezlotoxumab were found between patients with hepatic impairment and patients with normal hepatic function.
The effect of age on the pharmacokinetics of bezlotoxumab was evaluated in patients ranging from 18 to 100 years of age. No clinically meaningful differences in the exposure of bezlotoxumab were found between elderly patients 65 years and older and patients under 65 years of age.
Non-clinical data reveal no special hazard for humans based on conventional studies of repeated dose toxicity. Genotoxicity and carcinogenic potential have not been evaluated.
Animal reproduction or developmental toxicity studies have not been conducted with bezlotoxumab. There were no notable effects in the male and female reproductive organs in mice based on repeat dose toxicity studies and no binding to reproductive tissues was observed in tissue cross-reactivity studies.
© All content on this website, including data entry, data processing, decision support tools, "RxReasoner" logo and graphics, is the intellectual property of RxReasoner and is protected by copyright laws. Unauthorized reproduction or distribution of any part of this content without explicit written permission from RxReasoner is strictly prohibited. Any third-party content used on this site is acknowledged and utilized under fair use principles.
