Omadacycline Pharmacokinetics: Influence of Mortality Risk Score among Patients with Community-Acquired Bacterial Pneumonia

Omadacycline is approved in the United States to treat patients with communityacquired bacterial pneumonia (CABP) (1). In the phase 3 OPTIC study, a difference in mortality between omadacyclineand moxifloxacin-treated patients with CABP was noted (2). However, subsequent analyses found no differences between treatment groups to explain this mortality imbalance (3). The assessment of an exposure-response relationship for mortality among omadacycline-treated patients was not possible given few deaths (8 of 386) and that measured omadacycline concentrations were available for only 50 patients, none of whom died. However, to understand whether the risk of mortality is associated with omadacycline exposure, the influence of the baseline Pneumonia Patient Outcomes Research Team (PORT) risk class (4) and CURB-65 score (based on confusion, urea, respiratory rate, blood pressure, and age of$65) (5) on the pharmacokinetics (PK) of omadacycline for the 50 patients was evaluated. Summaries of baseline patient descriptors, stratified by the risk scores, are presented for the above-described 50 patients in Table S1 in the supplemental material. Table 1 shows the mean (standard deviation [SD]) day 1 omadacycline total-drug plasma AUC0–24 (area under the concentration-time curve from 0 to 24 h) values by the risk scores. Given that the results of a previous covariate analysis showed that females have significantly slower clearance thanmales (6), box-and-whisker plots showing the distributions of AUC0–24 stratified by sex and each risk score are provided in Fig. 1. Copyright © 2022 Trang et al. This is an openaccess article distributed under the terms of the Creative Commons Attribution 4.0 International license.

The authors declare a conflict of interest.M.T., M.C.S., J.P.H., S.M.B., and C.M.R. are employees of the Institute for Clinical Pharmacodynamics, Inc., which has received research support from Paratek Pharmaceuticals, Inc. E.A.L. was an employee of ICPD at the time the analyses were performed and is now and employee of Vertex Pharmaceuticals, Inc. L.F. was an employee of Paratek Pharmaceuticals, Inc., at the time the analyses were performed and is now an employee of AN2 Therapeutics.J.N.S. was an employee of Paratek Pharmaceuticals, Inc., at the time the analyses were performed and is now an employee of Scientific and Medical Affairs Consulting, LLC.P.C.M. was an employee of Paratek Pharmaceuticals, Inc., at the time the analyses were performed and is now an employee of VenatoRx, Inc., and E.T. was an employee of Paratek Pharmaceuticals, Inc., at the time the analyses were performed and is now an employee of Neuraptive Therapeutics, Inc.
Published 19 December 2022 LETTER TO THE EDITOR Two-way analysis of variance (ANOVA), adjusting for sex, was performed to assess the relationships between AUC 0-24 and each risk score.Based on the models summarized in Table S2, the mean AUC 0-24 values were lower for males than females (P # 0.002), and there was evidence of a sex-adjusted difference in the mean AUC 0-24 values between PORT risk classes II and IV (P = 0.019).Interactions between sex and each risk score were investigated but were not statistically significant (P $ 0.287) and were not retained in the models.
Estimates for the sex-adjusted pairwise group differences in the mean AUC 0-24 based on the two-way ANOVA are provided in Table 1.Based on the 95% confidence intervals, the largest estimated magnitudes were no more than 39.3 and 46.1% of the group means for PORT risk class and CURB-65 score, respectively.Since the AUC/MIC ratio is the pharmacokineticpharmacodynamic index that predicts efficacy for omadacycline, differences in the mean AUC 0-24 of at least halving or doubling are required to account for a full dilution change in the MIC when evaluating the probability of achieving AUC/MIC ratio targets associated with a 1-log 10 CFU reduction from baseline for Streptococcus pneumoniae or Haemophilus influenzae for the treatment of patients with CABP (7).In light of these considerations, the magnitude of differences based on the risk scores was not considered clinically relevant.
The number of patients with measured omadacycline concentrations (50/386) was one limitation of these analyses.Compared to the remaining patients in the intent-to-treat population, this subset was younger with a higher mean baseline creatinine clearance and a reduced history of hypertension.No other statistically significant differences were found, including those based on sex, PORT risk class, and CURB-65 score.Given this limitation, further PK assessments among omadacycline-treated patients with CABP should be carried out to confirm the findings described herein.
These findings suggest that the observed mortality imbalance was not due to differences in omadacycline PK.

SUPPLEMENTAL MATERIAL
Supplemental material is available online only.SUPPLEMENTAL FILE 1, PDF file, 0.1 MB.

ACKNOWLEDGMENT
This work was supported by Paratek Pharmaceuticals, Inc., King of Prussia, Pennsylvania, USA.

FIG 1
FIG 1Box-and-whisker plot showing the distribution of day 1 omadacycline total-drug plasma AUC 0-24 , stratified by sex and each PORT risk class and CURB-65 score.The upper and lower edges of each box represent the 25th and 75th percentiles of the distribution of total-drug plasma AUC 0-24 , respectively.The line within each box represents the median total-drug plasma AUC 0-24 value.The upper and lower whiskers extend to the furthest observed values within 1.5 Â IQR of the respective box edges (where IQR is defined as the difference between the 25 th and 75 th percentiles).