Date of Award

5-2023

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Program

Pharmaceutical Sciences

Track

Pharmacometrics

Research Advisor

Bernd Meibohm, PhD

Committee

Mercedes Gonzalez-Juarrero, PhD; Ying Kong, PhD; Santosh Kumar, PhD; Carl Panetta, PhD

Keywords

Mycobacterial Subpopulations, PK/PD, Spectinamide 1599, Tuberculosis

Abstract

Tuberculosis is one of the top 10 causes of death worldwide and the leading cause of death from a single infectious agent prior to COVID19. Mycobacterium tuberculosis (Mtb) is the causative agent of TB. The interaction between Mtb and the immune system leads to development of diverse environmental niches and physiology within the lung of the TB patients. Mtb is thought to adapt and thrive in such an environment by transforming to different phenotypic variants. Such variants are difficult to kill and are thought to prolong TB pharmacotherapy. Spectinamide 1599 is a synthetic modification of spectinomycin that has demonstrated excellent preclinical drug like properties such as excellent in vivo efficacy, strong efficacy against clinical MDR isolates, lack of cross resistance, long post antibiotic effect, and low toxicity potential. It also has a favorable pharmacokinetic profile and is primarily eliminated in the urine and thus has a low propensity for drug-drug interaction with other partner drugs. In addition, spectinamide 1599 has shown good lung penetration, good accumulation within lungs of mice over multiple doses, and high uptake into macrophages. In the first set of studies, we characterized the activity of spectinamide 1599 against log, acid and hypoxic phenotypic variants of Mtb using various in vitro approaches involving static and dynamic drug concentrations over time. We used minimum inhibitory concentration (MIC) and dose response studies to characterize the activity of spectinamide 1599 against log, acid, and hypoxic phenotypic variants. We found that, spectinamide 1599 has an MIC of 0.78 µg/mL against log phase bacteria and 6.25 µg/mL against acid phase bacteria. We then used the hollow fiber infection model (HFIM) as a dynamic pharmacokinetic (PK) and pharmacodynamics (PD) model system to evaluate the activity of spectinamide 1599 against log and acid phase bacteria. Our results show that spectinamide 1599 exhibits a potent dose-dependent bactericidal effect against log phase bacteria, but has limited effect against acid phase bacteria. We built a PK/PD model to characterize the activity of spectinamide 1599 against log and acid phase bacteria through estimated parameters. In the next set of studies, we attempted to integrate available preclinical data through a meta-analysis PK/PD model-based approach to quantitatively screen and characterize ternary drug combinations containing spectinamide 1599 in BALB/c mouse models of TB. The metanalysis process involved building models to describe natural growth of mycobacteria in the lungs of mice, the PK/PD effect of single and binary anti-TB drug regimens on growth of mycobacteria over time. The natural growth, single and pairwise drug model parameters were then used to predict bacterial kill for ternary drug combinations containing spectinamide 1599 using the Isserelis theorem. Once we achieved reasonable prediction of ternary drug combinations containing spectinamide 1599, we simulated bacterial kill of other ternary drug combination regimens to screen and rank combinations and create a framework to prioritize which combinations should be explored first in mouse models of TB. Altogether, the results of the above studies can be used as a roadmap or guide the optimization of spectinamide 1599’s dosing regimen in the preclinical development phase.

Declaration of Authorship

Declaration of Authorship is included in the supplemental files.

ORCID

https://orcid.org/0000-0003-2315-0100

DOI

10.21007/etd.cghs.2023.0625

Additional Files
2023-012-Temrikar-DOA.pdf (107 kB)
Declaration of Authorship
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