in#
21.6 (22/102)
32.2 (37/115)
-10.6 (-22.1, 1.3)
Infected with 027 ribotype
23.6 (21/89)
34.0 (34/100)
-10.4 (-23.0, 2.6)
n = Number of patients within subgroup that met the criteria for endpoint
m = Number of patients within subgroup
* Full Analysis Set = a subset of all randomised patients with exclusions for: (i) did not receive infusion of study medication, (ii) did not have a positive local stool test for toxigenic C. difficile; (iii) did not receive protocol defined standard of care therapy within a 1 day window of the infusion
† SoC = Standard of Care antibacterial (metronidazole or vancomycin or fidaxomicin)
‡ Based on the Miettinen and Nurminen method without stratification
§ Based on medical conditions or medications received that may result in immunosuppression
¶ Zar score ≥ 2
# Hypervirulent strain included the following: 027, 078, or 244 ribotypes
In the studies, the clinical cure rates of the presenting CDI episode were comparable between the treatment arms.
Immunogenicity
Immunogenicity of ZINPLAVA was eva luated using an electrochemiluminescence (ECL) assay in MODIFY I and MODIFY II.
Following treatment with ZINPLAVA in MODIFY I and MODIFY II, none of the 710 eva luable patients tested positive for treatment-emergent anti-bezlotoxumab antibodies. Although ZINPLAVA is intended for single dose administration, the immunogenicity of bezlotoxumab following a second administration of 10 mg/kg, 12 weeks after the first dose, was assessed in 29 healthy subjects. No anti-bezlotoxumab antibodies were detected after the second dose.
There are no data on repeated administration of bezlotoxumab in patients with CDI.
Paediatric population
The European Medicines Agency has deferred the obligation to submit the results of studies with ZINPLAVA in one or more subsets of the paediatric populations for the prevention of recurrence of Clostridium difficile infection (see section 4.2 for information on paediatric use).
5.2 Pharmacokinetic properties
Absorption
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.
Distribution
Bezlotoxumab has limited extravascular distribution. The mean volume of distribution of bezlotoxumab was 7.33 L (CV: 16 %).
Biotransformation
Bezlotoxumab is catabolized through protein degradation processes; metabolism does not contribute to its clearance.
Elimination
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 (t½) was approximately 19 days (28 %).
Special populations
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 impai |
