Combined quantitative tuberculosis biomarker model for time-to-positivity and colony forming unit to support tuberculosis drug development

Rami Ayoun Alsoud; Robin J Svensson; Elin M Svensson; Stephen H Gillespie; Martin J Boeree; Andreas H Diacon; Rodney Dawson; Rob E Aarnoutse; Ulrika S H Simonsson

doi:10.3389/fphar.2023.1067295

Combined quantitative tuberculosis biomarker model for time-to-positivity and colony forming unit to support tuberculosis drug development

Front Pharmacol. 2023 Mar 14:14:1067295. doi: 10.3389/fphar.2023.1067295. eCollection 2023.

Authors

Affiliations

¹ Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden.
² Department of Pharmacy, Uppsala University, Uppsala, Sweden.
³ Department of Pharmacy, Radboud Institute for Health Sciences, Radboud University Medical Center, Nijmegen, Netherlands.
⁴ Division of Infection and Global Health, School of Medicine, University of St Andrews, St Andrews, United Kingdom.
⁵ Department of Lung Diseases, Radboud University Medical Center, Nijmegen, Netherlands.
⁶ TASK Applied Science, Cape Town, South Africa.
⁷ Division of Pulmonology, Department of Medicine, University of Cape Town, Cape Town, South Africa.
⁸ University of Cape Town Lung Institute, Cape Town, South Africa.

Abstract

Biomarkers are quantifiable characteristics of biological processes. In Mycobacterium tuberculosis, common biomarkers used in clinical drug development are colony forming unit (CFU) and time-to-positivity (TTP) from sputum samples. This analysis aimed to develop a combined quantitative tuberculosis biomarker model for CFU and TTP biomarkers for assessing drug efficacy in early bactericidal activity studies. Daily CFU and TTP observations in 83 previously patients with uncomplicated pulmonary tuberculosis after 7 days of different rifampicin monotherapy treatments (10-40 mg/kg) from the HIGHRIF1 study were included in this analysis. The combined quantitative tuberculosis biomarker model employed the Multistate Tuberculosis Pharmacometric model linked to a rifampicin pharmacokinetic model in order to determine drug exposure-response relationships on three bacterial sub-states using both the CFU and TTP data simultaneously. CFU was predicted from the MTP model and TTP was predicted through a time-to-event approach from the TTP model, which was linked to the MTP model through the transfer of all bacterial sub-states in the MTP model to a one bacterial TTP model. The non-linear CFU-TTP relationship over time was well predicted by the final model. The combined quantitative tuberculosis biomarker model provides an efficient approach for assessing drug efficacy informed by both CFU and TTP data in early bactericidal activity studies and to describe the relationship between CFU and TTP over time.

Keywords: CFU; TTP; biomarker; rifampicin; tuberculosis.

Grants and funding

This clinical trial was conducted within PanACEA, which was part of the European and Developing Countries Clinical Trials Partnership (EDCTP) 1 programme [project code IP. 2007.32011.012 (HIGHRIF)] and the EDCTP2 programme supported by the European Union (grant number TRIA 2015-1102-PanACEA).