Population Pharmacokinetic Analyses for Omadacycline Using Phase 1 and 3 Data

Abstract

Omadacycline, a novel aminomethylcycline antibiotic with activity against Gram-positive and -negative organisms, including tetracycline-resistant pathogens, received FDA approval in October 2018 for the treatment of patients with acute bacterial skin and skin structure infections (ABSSSI) and community-acquired bacterial pneumonia (CABP). A previously developed population pharmacokinetic (PK) model based on phase 1 intravenous and oral PK data was refined using data from infected patients. Data from 10 phase 1 studies used to develop the previous model were pooled with data from three additional phase 1 studies, a phase 1b uncomplicated urinary tract infection study, one phase 3 CABP study, and two phase 3 ABSSSI studies. The final population PK model was a three-compartment model with first-order absorption using transit compartments to account for absorption delay following oral dosing and first-order elimination. Epithelial lining fluid (ELF) concentrations were modeled as a subcompartment of the first peripheral compartment. A food effect on oral bioavailability was included in the model. Sex was the only significant covariate identified, with 15.6% lower clearance for females than males. Goodness-of-fit diagnostics indicated a precise and unbiased fit to the data. The final model, which was robust in its ability to predict plasma and ELF exposures following omadacycline administration, was also able to predict the central tendency and variability in concentration-time profiles using an external phase 3 ABSSSI data set. A population PK model, which described omadacycline PK in healthy subjects and infected patients, was developed and subsequently used to support pharmacokinetic-pharmacodynamic (PK-PD) and PK-PD target attainment assessments.

Penetration of Antibacterial Agents into Pulmonary Epithelial Lining Fluid: An Update

“…Once protein binding estimates were accounted for (approximately 21% and approximately 80% for omadacycline and tigecycline, respectively), the total drug ELF to unbound serum penetration ratios were 1.84 for omadacycline and 6.59 for tigecycline [94]. Lakota and colleagues conducted a population PK analysis for omadacycline using the same omadacycline ELF data and plasma concentration-time data from phase I and III clinical research studies [95]. The total drug ELF to unbound plasma penetration ratio based on AUC 24 values at day 4 of therapy was calculated to be 2.06.…”

Safety and efficacy of omadacycline by BMI categories and diabetes history in two Phase III randomized studies of patients with acute bacterial skin and skin structure infections

“…Previous PK modelling has not identified high BMI or diabetes as covariates of interest, which potentially negates this concern. 22 , 23 Finally, this analysis was based on well-defined study populations that may not reflect all patient populations that are treated with these antimicrobial agents.…”

Omadacycline Oral Dosing and Pharmacokinetics in Community-Acquired Bacterial Pneumonia and Acute Bacterial Skin and Skin Structure Infection

“…All participants received a loading dose of omadacycline (300 mg orally twice on Day 1), followed by maintenance treatment of 300 mg orally once daily (qd), for a total treatment duration of 7–10 days [ 10 ]. The loading dose was selected to closely match the reference IV regimen for bioequivalence: 100 mg IV given twice on Day 1, the FDA-approved IV loading dose for both CABP and ABSSSI [ 1 , 2 , 7 , 10 , 11 ].…”

“…Previous studies have shown that there was no significant interaction of omadacycline with a broad range of membrane transporters, suggesting that drug–drug interactions based on the inhibition or induction of human drug transporter activity are unlikely with omadacycline when given at therapeutic concentrations [ 7 , 14 ]. The bioavailability of oral omadacycline is 34.5%; omadacycline is not metabolized, and oral omadacycline is primarily eliminated in the feces [ 4 , 7 , 11 , 15 ]. Previous Phase 1 and Phase 3 studies of omadacycline showed that no dose adjustments are necessary for any patient group, such as people with hepatic or renal impairment, including end-stage renal disease (ESRD) and those receiving dialysis [ 4 , 6 , 13 ]; dose adjustments are also unnecessary by body mass index [ 13 , 16 , 17 ] or older age [ 1 ].…”