A Pharmacometric Comparison of Omadacycline and Tigecycline Epithelial Lining Fluid (ELF) Penetration

Abstract

Background. Omadacycline, a novel aminomethylcycline antibiotic active against Gram‐positive and Gram‐negative organisms, is in development for the treatment of patients with acute bacterial skin and skin structure infections and community‐acquired bacterial pneumonia (CABP). Data from a Phase 1 ELF study were used to develop population PK models to describe the time course of omadacycline and tigecycline in both plasma and ELF. Methods. Subjects were randomized to receive either omadacycline 100 mg IV q12h × 2 doses followed by 100 mg q24h or tigecycline 100 mg IV x 1 then 50 mg q12h (42 and 21 subjects, respectively). Plasma and ELF samples were collected on Day 4 of therapy. Population PK models were fit to the collected data using NONMEN 7.2. The structural models for plasma were based on previously published population PK models [ECCMID 2016, Abstr P1320; AAC 2006; 50:3701‐7]. Various structural models were evaluated for the characterization of ELF concentrations. Day 4 total‐drug ELF and total‐ and free‐drug plasma AUC values were computed using numeric integration; these data were used to determine ELF penetration ratios. A fixed protein binding estimate (20%) was used for omadacycline while a non‐linear function was used to describe tigecycline's protein binding [AAC 2010; 54:5209‐13]. Results. Linear three‐ and two‐compartment models with ELF incorporated into the first peripheral compartment best described the omadacycline and tigecycline PK data, respectively. The ELF visual predictive checks displayed in Figure 1 show that the models accurately captured the omadacycline and tigecycline ELF concentration‐time profiles. Model‐computed omadacycline and tigecycline totaldrug ELF AUC to total‐drug plasma AUC ratios were 1.54 and 1.16, respectively. Model‐computed total‐drug ELF AUC to free‐drug plasma AUC ratios were 1.93 and 1.87, respectively. Conclusion. Population PK models were successfully developed to characterize the disposition of both omadacycline and tigecycline in plasma and ELF. When assessed relative to free‐drug plasma exposures, omadacycline and tigecycline demonstrated similar ELF penetration. Use of these data with PK‐PD target attainment analyses will be useful to support omadacycline dose selection for CABP. (Table Presented).