Population Pharmacokinetic Analyses for Omadacycline Using Phase 1 and 3 Data.
Elizabeth A Lakota, Scott A Van Wart, Michael Trang, Evan Tzanis, Sujata M Bhavnani, M Courtney Safir, Lawrence Friedrich, Judith N Steenbergen, Paul G Ambrose, Christopher M Rubino
Author Information
Elizabeth A Lakota: Institute for Clinical Pharmacodynamics, Inc., Schenectady, New York, USA.
Scott A Van Wart: Institute for Clinical Pharmacodynamics, Inc., Schenectady, New York, USA.
Michael Trang: Institute for Clinical Pharmacodynamics, Inc., Schenectady, New York, USA.
Evan Tzanis: Paratek Pharmaceuticals, King of Prussia, Pennsylvania, USA.
Sujata M Bhavnani: Institute for Clinical Pharmacodynamics, Inc., Schenectady, New York, USA.
M Courtney Safir: Institute for Clinical Pharmacodynamics, Inc., Schenectady, New York, USA.
Lawrence Friedrich: Paratek Pharmaceuticals, King of Prussia, Pennsylvania, USA.
Judith N Steenbergen: Paratek Pharmaceuticals, King of Prussia, Pennsylvania, USA.
Paul G Ambrose: Institute for Clinical Pharmacodynamics, Inc., Schenectady, New York, USA.
Christopher M Rubino: Institute for Clinical Pharmacodynamics, Inc., Schenectady, New York, USA crubino@icpd.com.
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.
