734. Modeling the Pharmacokinetics and Pharmacodynamics of Intravenous and Oral Omadacycline with and without a Loading Dose

BACKGROUND: Omadacycline (OMC) is an intravenous (IV) and oral aminomethylcycline antibiotic in the tetracycline class approved in the United States to treat acute bacterial skin and skin structure infections (ABSSSI) and community-acquired bacterial pneumonia (CABP) in adults. The approved dosing regimens of OMC include a loading dose designed to achieve steady-state exposures early in the course of therapy. We assessed the impact on OMC exposure and subsequent pharmacodynamics (PD) on Day 2 and at steady state (Day 5) in the situation where a loading dose may not be given. METHODS: Phase 1 pharmacokinetic (PK) data were used to determine OMC exposure on Day 2 and at steady state (Day 5) for the following: IV regimens 100 mg IV q12h on Day 1 then 100 mg IV QD (load), 100 mg IV QD (no load); and oral regimens 450 mg oral QD on Days 1 and 2 then 300 mg QD (load) and 300 mg oral QD (no load). AUCs on Day 2 and Day 5 for no-load regimens were compared with the regimens with loading doses. Additionally, AUC:MIC ratios were calculated using OMC MIC(90) for two main pathogens of interest in ABSSSI and CABP, respectively, Staphylococcus aureus (0.25 mg/L) and Streptococcus pneumoniae (0.12 mg/L). In vivo AUC:MIC targets for stasis and 1-log kill used were 21.9 and 57.7 (S. aureus) and 31.2 and 65.8 (S. pneumoniae). RESULTS: Day 2 and 5 AUCs are shown in the Figure. AUCs on Day 2 were lower for the two regimens without loading doses and were 72% (IV) and 73% (oral) of those with a loading dose. However, at steady state on Day 5, no-load regimen AUCs were essentially the same at 98% for both the IV and oral regimens. Despite lower AUCs on Day 2 for the no-load regimens, the AUC:MIC ratio would still be expected to exceed the stasis threshold for both pathogens and the 1-log kill threshold for S. pneumoniae (figure). This same pattern was also noted on Day 5. CONCLUSION: Exposure as assessed using AUC was lower early on in therapy on Day 2 for both IV and oral regimens. However, exposures were not different on Day 5 at steady state. Despite lower exposure on Day 2, OMC would still be expected to meet or exceed PK/PD thresholds associated with stasis for S. aureus and S. pneumoniae. The 1-log kill threshold was exceeded for S. pneumoniae. Further studies are needed to confirm any clinical impact of the omission of OMC loading doses. [Image: see text] DISCLOSURES: All authors: No reported disclosures.