Laurynas Mockeliunas: Pharmacometric efficacy and safety evaluations within the fields of pulmonary tuberculosis and COVID-19

Abstract

Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis. Each year, more than 10 million people are estimated to develop TB, and over 1.2 million die from the disease, and resistance to drugs is a major challenge. Another infectious disease, coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), resulted in over 700 million infections and nearly 7 million deaths worldwide over several years. The aim of this thesis was to use pharmacometric methods to evaluate the efficacy and safety of drugs for tuberculosis and the efficacy of a repurposed vaccine for COVID-19.

To improve TB drug development, a standardized pharmacometric model-based early bactericidal activity (EBA) analysis workflow was established to analyze EBA trials, and sample size calculations were performed to inform future EBA trial designs. Application of this workflow to a conducted EBA trial revealed that adding rifampicin to meropenem (administered with amoxicillin and clavulanic acid) did not enhance short-term activity in patients with rifampicin-resistant TB.

Furthermore, pharmacometric modelling and simulation were used to optimize MDR-TB treatment with linezolid. A model-informed precision dosing algorithm was developed, enabling individualized dosing from the first day of treatment, enabling both efficacious and safe treatment. Safety targets for linezolid-related adverse events, such as anemia, thrombocytopenia, and peripheral neuropathy were also established, providing more information on the adverse events linked to linezolid.

Finally, a reproducible pharmacometric workflow was implemented to facilitate data processing, reporting, and analysis of a phase 3 trial assessing whether the repurposed Bacillus Calmette-Guérin TB vaccine could reduce morbidity and mortality from COVID-19 and respiratory tract infections (RTIs). Pharmacometric analysis of this trial allowed for the identification of the risk factors for COVID-19 and RTIs in frontline healthcare workers.

In summary, this thesis used pharmacometric methods to optimize the EBA evaluations in TB with a standardized EBA workflow and to develop an algorithm for individualized precision dosing of linezolid in patients with MDR-TB. Furthermore, pharmacometric modelling enabled efficacy evaluation of a repurposed TB vaccine against COVID-19 and confirmation of risk factors for RTIs and COVID-19 in frontline healthcare workers.