Determination of the Pharmacokinetics and Pharmacodynamics of Isoniazid, Rifampicin, Pyrazinamide and Ethambutol in a Cross-Over Cynomolgus Macaque Model of Infection.
Laura Sibley, Andrew D White, Charlotte Sarfas, Jennie Gullick, Fergus Gleeson, Faye Lanni, Simon Clark, Emma Rayner, Santiago Ferrer-Bazaga, Fatima Ortega-Muro, Laura Alameda, Joaquin Rullas, Veronica Sousa, Marisa Martinez, Inigo Angulo-Barturen, Adolfo Garcia, Juan José Vaquero, Henry E Pertinez, Geraint Davies, Mike Dennis, Ann Williams, Sally Sharpe
Author Information
Laura Sibley: UK Health Security Agency, Research and Evaluation, Porton Down, Salisbury SP4 0JG, UK.
Andrew D White: UK Health Security Agency, Research and Evaluation, Porton Down, Salisbury SP4 0JG, UK. ORCID
Charlotte Sarfas: UK Health Security Agency, Research and Evaluation, Porton Down, Salisbury SP4 0JG, UK.
Jennie Gullick: UK Health Security Agency, Research and Evaluation, Porton Down, Salisbury SP4 0JG, UK.
Fergus Gleeson: Department of Oncology, Medical Sciences Division, Churchill Hospital, Oxford OX3 7DQ, UK.
Faye Lanni: UK Health Security Agency, Research and Evaluation, Porton Down, Salisbury SP4 0JG, UK.
Simon Clark: UK Health Security Agency, Research and Evaluation, Porton Down, Salisbury SP4 0JG, UK.
Emma Rayner: UK Health Security Agency, Research and Evaluation, Porton Down, Salisbury SP4 0JG, UK.
Santiago Ferrer-Bazaga: Departmento de Bioingenieria, Universidad Carlos III de Madrid, 28903 Madrid, Spain. ORCID
Fatima Ortega-Muro: GlaxoSmithKlein, Research and Development, Diseases of the Developing World, Severo Ochoa, 2., 28760 Madrid, Spain.
Laura Alameda: GlaxoSmithKlein, Research and Development, Diseases of the Developing World, Severo Ochoa, 2., 28760 Madrid, Spain.
Joaquin Rullas: GlaxoSmithKlein, Research and Development, Diseases of the Developing World, Severo Ochoa, 2., 28760 Madrid, Spain.
Veronica Sousa: GlaxoSmithKlein, Research and Development, Diseases of the Developing World, Severo Ochoa, 2., 28760 Madrid, Spain.
Marisa Martinez: GlaxoSmithKlein, Research and Development, Diseases of the Developing World, Severo Ochoa, 2., 28760 Madrid, Spain.
Inigo Angulo-Barturen: GlaxoSmithKlein, Research and Development, Diseases of the Developing World, Severo Ochoa, 2., 28760 Madrid, Spain. ORCID
Adolfo Garcia: GlaxoSmithKlein, Research and Development, Diseases of the Developing World, Severo Ochoa, 2., 28760 Madrid, Spain.
Juan José Vaquero: Departmento de Bioingenieria, Universidad Carlos III de Madrid, 28903 Madrid, Spain. ORCID
Henry E Pertinez: Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool L69 3GX, UK.
Geraint Davies: Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool L69 3GX, UK.
Mike Dennis: UK Health Security Agency, Research and Evaluation, Porton Down, Salisbury SP4 0JG, UK.
Ann Williams: UK Health Security Agency, Research and Evaluation, Porton Down, Salisbury SP4 0JG, UK.
Sally Sharpe: UK Health Security Agency, Research and Evaluation, Porton Down, Salisbury SP4 0JG, UK.
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 (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.
