Date of Award

1-2023

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Program

Pharmaceutical Sciences

Track

Pharmacometrics

Research Advisor

Bernd Meibohm, PhD

Committee

Andrea N. Edginton, PhD; Santosh Kumar, PhD; Glen E. Palmer, PhD; Carl J. Panetta, PhD

Keywords

granuloma model, interspecies extrapolation, intratracheal PBPK, mPBPK, spectinamides, subcutaneous PBPK

Abstract

Despite being an ancient disease caused by Mycobacterium tuberculosis (Mtb) and after decades of research, tuberculosis (TB) still affects millions of people every year worldwide. In 2018, the World Health Organization (WHO) reported that 10 million people developed tuberculosis and 1.5 million died of the disease. With the increase in the multidrug-resistant (MDR) and extensively drug-resistant (XDR) cases, the treatment for TB with the standard first and second-line therapy is becoming increasingly difficult. Therefore, there is an urgent need to find new anti-TB drugs as combination partners of existing and experimental classes of antimicrobial agents to shorten and simplify the treatment of MDR or XDR TB infection. Spectinamide 1599 and spectinamide 1810 are lead spectinamide compounds currently under preclinical development for the treatment of MDR and XDR tuberculosis. These compounds have previously been tested at various combinations of dose level, dosing frequency, and routes of administration in mouse models of Mtb infection and in healthy animals. Characterizing the disposition of a compound in the tissues of interest is important in understanding the pharmacology of novel antibiotic agents. TB is primarily a pulmonary disease, but extrapulmonary disease has been reported in 10-42% of patients. Thus, understanding the drug disposition and exposure in the tissues in which Mtb is residing is of utmost importance for any new antitubercular drug. Hence, we have used a physiologically-based pharmacokinetic (PBPK) approach for the prediction of drug pharmacokinetics in organs/tissues of interest and extrapolate their disposition across different species. In the current study, we built, qualified, and refined a minimalistic PBPK model that can describe and predict the pharmacokinetics of spectinamide antibiotics in various tissue, especially those relevant to Mtb infection. The model was expanded and qualified for multiple dose levels, dosing regimens, routes of administration, and various species. The model predictions in mice (healthy and infected) and rats were in reasonable agreement, and all predicted Area Under the Curve (AUCs) in plasma and tissues met the twofold acceptance criteria relative to observed data. To further explore tissue exposure in Mtb lesions, we also utilized the established Simcyp granuloma model to explore the distribution of spectinamide 1599 within granuloma substructures. Simulation results suggest substantial exposure in all lesion substructures, with particularly high exposure in the rim region and in macrophages of the lesion. The developed model may be leveraged as an effective tool in predicting the disposition of spectinamide antibiotics in further preclinical and clinical development to identify optimal dose levels and dosing regimens.

Declaration of Authorship

Declaration of Authorship is included in the supplemental files.

ORCID

https://orcid.org/0000-0003-4127-4115

DOI

10.21007/etd.cghs.2023.0615

Additional Files
2023-002-Parmar-DOA.pdf (126 kB)
Declaration of Authorship
Model Script Supplemental Data File.pdf (75 kB)
Model Script Supplemental Data File
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