Population Pharmacokinetic Analyses for Omadacycline Using Phase 1 and 3 Data

Area of Science:

• Pharmacokinetics
• Antibiotic Development
• Infectious Diseases

Background:

• Omadacycline is a novel aminomethylcycline antibiotic approved for acute bacterial skin and skin structure infections (ABSSSI) and community-acquired bacterial pneumonia (CABP).
• A population pharmacokinetic (PK) model was previously developed using Phase 1 data.
• Refinement of the PK model is necessary to incorporate data from infected patient populations.

Purpose of the Study:

• To refine the existing population PK model for omadacycline.
• To incorporate data from healthy subjects and infected patients across various studies.
• To evaluate the model's ability to predict drug exposure and support PK-PD assessments.

Main Methods:

• Pooled data from multiple Phase 1, Phase 1b, and Phase 3 studies involving omadacycline.
• Developed a three-compartment population PK model with first-order absorption and elimination.
• Incorporated transit compartments for oral absorption delay, modeled epithelial lining fluid (ELF) concentrations, and included a food effect.
• Identified covariates influencing omadacycline PK, with sex being the only significant factor.

Main Results:

• The final population PK model accurately described omadacycline PK in both healthy subjects and infected patients.
• Sex was identified as a significant covariate, with females exhibiting 15.6% lower clearance than males.
• The model demonstrated a precise and unbiased fit to the data and robust predictive performance for plasma and ELF exposures.
• The model successfully predicted central tendency and variability in concentration-time profiles using external Phase 3 data.

Conclusions:

• A robust population PK model for omadacycline was developed, integrating data from diverse studies and populations.
• The model accurately predicts omadacycline exposure in plasma and ELF, accounting for factors like food intake and sex.
• This refined model is valuable for supporting pharmacokinetic-pharmacodynamic (PK-PD) analyses and target attainment assessments for omadacycline therapy.