Determination of the Pharmacokinetics and Pharmacodynamics of Isoniazid, Rifampicin, Pyrazinamide and Ethambutol in a Cross-Over Cynomolgus Macaque Model of <i>Mycobacterium tuberculosis</i> Infection



Sibley, Laura, White, Andrew D, Sarfas, Charlotte, Gullick, Jennie, Gleeson, Fergus, Lanni, Faye, Clark, Simon, Rayner, Emma, Ferrer-Bazaga, Santiago, Ortega-Muro, Fatima
et al (show 12 more authors) (2022) Determination of the Pharmacokinetics and Pharmacodynamics of Isoniazid, Rifampicin, Pyrazinamide and Ethambutol in a Cross-Over Cynomolgus Macaque Model of <i>Mycobacterium tuberculosis</i> Infection. PHARMACEUTICS, 14 (12). 2666-.

[thumbnail of Sibley et al. (2022) NHP Tuberculosis PKPD.pdf] Text
Sibley et al. (2022) NHP Tuberculosis PKPD.pdf - Published version

Download (3MB) | Preview

Abstract

Innovative cross-over study designs were explored in non-human primate (NHP) studies to determine the value of this approach for the evaluation of drug efficacy against tuberculosis (TB). Firstly, the pharmacokinetics (PK) of each of the drugs Isoniazid (H), Rifampicin (R), Pyrazinamide (Z) and Ethambutol (E), that are standardly used for the treatment of tuberculosis, was established in the blood of macaques after oral dosing as a monotherapy or in combination. Two studies were conducted to evaluate the pharmacokinetics and pharmacodynamics of different drug combinations using cross-over designs. The first employed a balanced, three-period Pigeon design with an extra period; this ensured that treatment by period interactions and carry-over could be detected comparing the treatments HR, HZ and HRZ using H37Rv as the challenge strain of <i>Mycobacterium tuberculosis</i> (M. tb). Although the design accounted for considerable variability between animals, the three regimens evaluated could not be distinguished using any of the alternative endpoints assessed. However, the degree of pathology achieved using H37Rv in the model during this study was less than expected. Based on these findings, a second experiment using a classical AB/BA design comparing HE with HRZ was conducted using the M. tb Erdman strain. More extensive pathology was observed, and differences in computerized tomography (CT) scores and bacteriology counts in the lungs were detected, although due to the small group sizes, clearer differences were not distinguished. Type 1 T helper (Th1) cell response profiles were characterized using the IFN-γ ELISPOT assay and revealed differences between drug treatments that corresponded to decreases in disease burden. Therefore, the studies performed support the utility of the NHP model for the determination of PK/PD of TB drugs, although further work is required to optimize the use of cross-over study designs.

Item Type: Article
Uncontrolled Keywords: tuberculosis, antibiotics, pharmacokinetics, pharmacodynamics, primates
Divisions: Faculty of Health and Life Sciences
Faculty of Health and Life Sciences > Institute of Systems, Molecular and Integrative Biology
Depositing User: Symplectic Admin
Date Deposited: 06 Jan 2023 09:53
Last Modified: 18 Oct 2023 11:45
DOI: 10.3390/pharmaceutics14122666
Related URLs:
URI: https://livrepository.liverpool.ac.uk/id/eprint/3166801