The Pharmacokinetics of CPZEN-45, a Novel Anti-Tuberculosis Drug, in Guinea Pigs

Author:

Garcia-Contreras Lucila1ORCID,Hanif Shumaila Nida Muhammad12,Ibrahim Mariam13,Durham Phillip45,Hickey Anthony J.5

Affiliation:

1. Department of Pharmaceutical Sciences, College of Pharmacy, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73117, USA

2. Department of Biomedical Sciences, Kentucky College of Osteopathic Medicine, University of Pikeville, Pikeville, KY 41501, USA

3. AstraZeneca, One MedImmune Way, Gaithersburg, MD 20878, USA

4. Department of Biomedical Engineering, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA

5. RTI International, 3040 Cornwallis Road, Research Triangle Park, NC 27709, USA

Abstract

CPZEN-45 is a novel compound with activity against drug-susceptible and drug-resistant tuberculosis (TB). The present study was undertaken to determine the best dose and dosing regimen of inhalable CPZEN-45 powders to use in efficacy studies with TB-infected guinea pigs. The disposition of CPZEN-45 after intravenous, subcutaneous (SC), and direct pulmonary administration (INS) was first determined to obtain their basal pharmacokinetic (PK) parameters. Then, the disposition of CPZEN-45 powders after passive inhalation using consecutive and sequential doses was evaluated. Plasma concentration versus time curves and PK parameters indicated that the absorption of CPZEN-45 after INS was faster than after SC administration (Ka = 12.94 ± 5.66 h−1 and 1.23 ± 0.55 h−1, respectively), had a longer half-life (2.06 ± 1.01 h versus 0.76 ± 0.22 h) and had higher bioavailability (67.78% and 47.73%, respectively). The plasma concentration versus time profiles and the lung tissue concentration at the end of the study period were not proportional to the dose size after one, two, and three consecutive passive inhalation doses. Three sequential passive inhalation doses maintained therapeutic concentration levels in plasma and lung tissue for a longer time than three consecutive doses (10 h vs. 3 h, respectively). Future studies to evaluate the efficacy of inhaled CPZEN-45 powders should employ sequential doses of the powder, with one nominal dose administered to animals three times per day.

Funder

National Institute of Allergy and Infectious Disease

Publisher

MDPI AG

Subject

Pharmaceutical Science

Reference40 articles.

1. World Health Organization (2021). Global Tuberculosis Report 2021, WHO.

2. Crist, C. (2022). Worst TB Outbreak in 20 Years Reported in Washington State, Medscape.

3. Washington State Department of Health (2022). Tuberculosis Cases on the Rise Globally and in Washington State.

4. Treatment of Highly Drug-Resistant Pulmonary Tuberculosis;Conradie;N. Engl. J. Med.,2020

5. Linezolid for Treating Tuberculosis: A Delicate Balancing Act;Maartens;EBioMedicine,2015

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