Population pharmacokinetics and pharmacodynamics of bezlotoxumab in adults with primary and recurrent Clostridium difficile infection [Clinical Therapeutics]

The fully human monoclonal antibody bezlotoxumab is indicated for preventing recurrence of Clostridioides (formerly Clostridium) difficile infection (CDI) in adults receiving antibacterial treatment for CDI and at high risk for CDI recurrence. The efficacy and safety of 10 mg/kg bezlotoxumab was demonstrated in two Phase 3 trials: MODIFY I (NCT01241552) and MODIFY II (NCT01513239). Here, a population pharmacokinetic (popPK) analysis is reported using data from MODIFY I and II (n=1515), and from three Phase 1 trials (n=72) to characterize bezlotoxumab PK in Phase 3 clinical trial participants and in healthy subjects. A stepwise covariate search was conducted to identify factors influencing PK. Post-hoc estimated bezlotoxumab exposures from the popPK model were used to conduct an exposure-response analysis for CDI recurrence.

Bezlotoxumab PK was described by a two-compartment model with linear elimination and allometric scaling for clearance and volume of distribution by body weight. Although the final popPK model included gender, ethnicity (Japanese descent), race (black vs non-black), and albumin level as significant covariates, the impact of these factors was not clinically meaningful based on the totality of PK and clinical experience.

Exposure-response analysis of CDI recurrence demonstrated a similar low rate of CDI recurrence over the entire range of exposures achieved in the Phase 3 trials, indicating that exposures were on the maximal response plateau of the exposure-response curve. Overall, the analyses confirmed the appropriateness of the 10 mg/kg dose across the Phase 3 population with no dose adjustments necessary over a broad demographic background.

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