Population Pharmacokinetics and Pharmacodynamics of Bezlotoxumab in Adults with Primary and Recurrent Clostridium difficile Infection

Abstract

The fully human monoclonal antibody bezlotoxumab is indicated for preventing the recurrence of Clostridioides difficile (formerly Clostridium difficile) infection (CDI) in adults who receive antibacterial treatment for CDI and who are at high risk for a CDI recurrence. The efficacy and safety of 10-mg/kg of body weight bezlotoxumab were demonstrated in two phase 3 trials: the MODIFY I (ClinicalTrials.gov registration number NCT01241552) and MODIFY II (ClinicalTrials.gov registration number NCT01513239) trials. Here, a population pharmacokinetic (popPK) analysis, performed using data from the MODIFY I and II trials (n = 1,515) and from three phase 1 trials (n = 72) to characterize bezlotoxumab pharmacokinetics (PK) in phase 3 clinical trial participants and in healthy subjects, is reported. 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 were described by a two-compartment model with linear elimination and allometric scaling for clearance and the volume of distribution by body weight. Although the final popPK model included gender, ethnicity (Japanese descent), race (black versus nonblack), and albumin level as significant covariates, the impact of these factors was not clinically meaningful, based on the totality of the 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 trial population with no dose adjustments necessary over a broad demographic background.

Keywords: Clostridium difficile; bezlotoxumab; population pharmacokinetics.

Copyright © 2019 American Society for Microbiology.

Figures

FIG 1

Goodness-of-fit plots (a, b) and visual predictive check of phase 3 trial concentrations in participants receiving bezlotoxumab only (c) for the final bezlotoxumab popPK model. In panels a and b, dots are individual data; solid lines are the locally estimated scatterplot smoothing (LOESS) lines. In panel a, dashed lines are lines of unity; in panel b, dashed lines are thresholds for outliers (|CWRES| = 6); data for 5 samples from the MODIFY I and MODIFY II trials taken beyond day 200 are not shown in the plots. In panel c, circles represent observed data; light solid lines and light dashed lines are the observed median and observed 95% interval, respectively. Dark lines and dark dashed lines are the predicted median and predicted 95% interval, respectively. conc, concentration; CWRES, conditional weighted residuals; popPK, population pharmacokinetics.

FIG 2

Impact of intrinsic factors on bezlotoxumab AUC0–inf in the phase 3 trial population. AUC0–inf, area under the concentration-time curve from time zero to infinity; CDI, Clostridium difficile infection; GMR, geometric mean ratio; CI, confidence interval; Ph1, phase 1; popPK, population pharmacokinetics; RI, renal impairment; ESRD, end-stage renal disease.

FIG 3

Association of bezlotoxumab exposure with the albumin level. (a) Bezlotoxumab AUC0–inf by albumin levels in phase 3 trial participants and healthy subjects. (b) Bezlotoxumab AUC0–inf by albumin levels in phase 3 trial participants and healthy subjects after albumin normalization. (c) Effect of albumin on bezlotoxumab CL in phase 3 trial participants and healthy subjects. (d) Effect of albumin on the bezlotoxumab Vc in phase 3 trial participants and healthy subjects. The line with a shaded area represents the change in the pharmacokinetic parameter (CL or Vc) as a function of the covariate value; the shaded area represents the 90% confidence interval based on uncertainty; thick dashed lines represent body weight effects in the case of a scaling coefficient of 0.75 and 1 for CL and Vc, respectively. AUC0–inf, area under the concentration-time curve from time zero to infinity; CL, clearance; P05, 5th percentile; P95, 95th percentile; Vc, central volume of distribution.

FIG 4

Association of CDI recurrence rate by bezlotoxumab exposure quartile (a) and CDI recurrence rate by albumin level quartile (b). ACT, actoxumab; AUC0–inf, area under the concentration-time curve from time zero to infinity; BEZ, bezlotoxumab; CDI, Clostridium difficile infection.

FIG 5

Sensitivity analysis of CDI recurrence rate by bezlotoxumab exposure quartile (a) and CDI recurrence rate by albumin level quartile (b). Participants who discontinued or died were considered as having a CDI recurrence, in addition to participants already classified as having a CDI recurrence according to the primary endpoint definition. ACT, actoxumab; AUC0–inf, area under the concentration-time curve from time zero to infinity; BEZ, bezlotoxumab; CDI, Clostridium difficile infection.

FIG 6

Observed and model-predicted maximal response in CDI recurrence rate across albumin-corrected bezlotoxumab AUC0–inf by decile following a single intravenous dose of 10-mg/kg bezlotoxumab. AUC0–inf, area under the concentration-time curve from time zero to infinity; CDI, Clostridium difficile infection; CI, confidence interval.