{"id":{"repo_id":"tenn-hsc","oai_identifier":"oai:dc.uthsc.edu:dissertations-1628"},"canonical_url":"https://search.dev.ndltd.org/etd/tenn-hsc/oai:dc.uthsc.edu:dissertations-1628","repository":{"repo_id":"tenn-hsc","name":"University of Tennessee Health Science Center","base_url":"https://dc.uthsc.edu/do/oai/"},"display":{"title":"Physiologically-Based Pharmacokinetic (PBPK) Modeling for the Preclinical Development of Spectinamide Antibiotics","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.","abstract_html":"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.","abstract_has_math":false,"creators":["Parmar, Keyur R."],"institution":null,"degree_name":"Doctor of Philosophy (PhD)","degree_level":"Dissertation","degree_discipline":"Pharmaceutical Sciences","degree_department":null,"school":null,"contributors":["Bernd Meibohm, PhD"],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2023,"date_issued":"2023-01-01T08:00:00Z","date_published":"2023-01-01T08:00:00Z","updated_at":"2026-07-24T05:00:53Z","subjects":["granuloma model","interspecies extrapolation","intratracheal PBPK","mPBPK","spectinamides","subcutaneous PBPK","Analytical, Diagnostic and Therapeutic Techniques and Equipment","Bacterial Infections and Mycoses","Diseases","Investigative Techniques","Medical Sciences","Medicine and Health Sciences","Other Pharmacy and Pharmaceutical Sciences","Pharmaceutics and Drug Design","Pharmacy and Pharmaceutical Sciences","Respiratory Tract Diseases","Therapeutics"],"languages":[],"rights":[],"rights_urls":[],"identifier_entries":[]},"links":{"outbound_url":"https://dc.uthsc.edu/dissertations/628","outbound_label":"Repository record","outbound_source":"dc:identifier"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor","label":"Contributor","values":["Bernd Meibohm, PhD"]},{"key":"dc:creator","label":"Author","values":["Parmar, Keyur R."]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date.available","label":"Dc Date Available","values":["2024-03-26T07:00:00Z"]},{"key":"thesis:degree_discipline","label":"Discipline","values":["Pharmaceutical Sciences"]},{"key":"thesis:degree_level","label":"Degree Level","values":["Dissertation"]},{"key":"thesis:degree_name","label":"Degree Name","values":["Doctor of Philosophy (PhD)"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["granuloma model","interspecies extrapolation","intratracheal PBPK","mPBPK","spectinamides","subcutaneous PBPK","Analytical, Diagnostic and Therapeutic Techniques and Equipment","Bacterial Infections and Mycoses","Diseases","Investigative Techniques","Medical Sciences","Medicine and Health Sciences","Other Pharmacy and Pharmaceutical Sciences","Pharmaceutics and Drug Design","Pharmacy and Pharmaceutical Sciences","Respiratory Tract Diseases","Therapeutics"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier","label":"Identifier","values":["https://dc.uthsc.edu/dissertations/628"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description.abstract","label":"Abstract","values":["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."]},{"key":"dc:title","label":"Title","values":["Physiologically-Based Pharmacokinetic (PBPK) Modeling for the Preclinical Development of Spectinamide Antibiotics"]}]}],"canonical_facts":{"dc:contributor":["Bernd Meibohm, PhD"],"dc:creator":["Parmar, Keyur R."],"dc:date.available":["2024-03-26T07:00:00Z"],"dc:description.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."],"dc:identifier":["https://dc.uthsc.edu/dissertations/628"],"dc:subject":["granuloma model","interspecies extrapolation","intratracheal PBPK","mPBPK","spectinamides","subcutaneous PBPK","Analytical, Diagnostic and Therapeutic Techniques and Equipment","Bacterial Infections and Mycoses","Diseases","Investigative Techniques","Medical Sciences","Medicine and Health Sciences","Other Pharmacy and Pharmaceutical Sciences","Pharmaceutics and Drug Design","Pharmacy and Pharmaceutical Sciences","Respiratory Tract Diseases","Therapeutics"],"dc:title":["Physiologically-Based Pharmacokinetic (PBPK) Modeling for the Preclinical Development of Spectinamide Antibiotics"],"thesis:degree_discipline":["Pharmaceutical Sciences"],"thesis:degree_level":["Dissertation"],"thesis:degree_name":["Doctor of Philosophy (PhD)"]},"updated_at":"2026-07-24T05:00:53Z"}