title: Pharmacokinetics-pharmacodynamics analysis of bicyclic 4-nitroimidazole analogs in a murine model of tuberculosis.
abstract: PA-824 is a bicyclic 4-nitroimidazole, currently in phase II clinical trials for the treatment of tuberculosis. Dose fractionation pharmacokinetic-pharmacodynamic studies in mice indicated that the driver of PA-824 in vivo efficacy is the time during which the free drug concentrations in plasma are above the MIC (fT>MIC). In this study, a panel of closely related potent bicyclic 4-nitroimidazoles was profiled in both in vivo PK and efficacy studies. In an established murine TB model, the efficacy of diverse nitroimidazole analogs ranged between 0.5 and 2.3 log CFU reduction compared to untreated controls. Further, a retrospective analysis was performed for a set of seven nitroimidazole analogs to identify the PK parameters that correlate with in vivo efficacy. Our findings show that the in vivo efficacy of bicyclic 4-nitroimidazoles correlated better with lung PK than with plasma PK. Further, nitroimidazole analogs with moderate-to-high volume of distribution and Lung to plasma ratios of >2 showed good efficacy. Among all the PK-PD indices, total lung T>MIC correlated the best with in vivo efficacy (rs = 0.88) followed by lung Cmax/MIC and AUC/MIC. Thus, lung drug distribution studies could potentially be exploited to guide the selection of compounds for efficacy studies, thereby accelerating the drug discovery efforts in finding new nitroimidazole analogs.
authors.affiliation: Novartis Institute for Tropical Diseases, Singapore, Singapore.
authors.forename: Suresh B
authors.initials: SB
authors.lastname: Lakshminarayana
authors.affiliation: Tuberculosis Research Section, Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Helena I M
authors.initials: HI
authors.lastname: Boshoff
authors.affiliation: Novartis Institute for Tropical Diseases, Singapore, Singapore.
authors.forename: Joseph
authors.initials: J
authors.lastname: Cherian
authors.affiliation: Novartis Institute for Tropical Diseases, Singapore, Singapore.
authors.forename: Sindhu
authors.initials: S
authors.lastname: Ravindran
authors.affiliation: Novartis Institute for Tropical Diseases, Singapore, Singapore.
authors.forename: Anne
authors.initials: A
authors.lastname: Goh
authors.affiliation: Novartis Institute for Tropical Diseases, Singapore, Singapore.
authors.forename: Jan
authors.initials: J
authors.lastname: Jiricek
authors.affiliation: Novartis Institute for Tropical Diseases, Singapore, Singapore.
authors.forename: Mahesh
authors.initials: M
authors.lastname: Nanjundappa
authors.affiliation: Tuberculosis Research Section, Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Amit
authors.initials: A
authors.lastname: Nayyar
authors.affiliation: Novartis Institute for Tropical Diseases, Singapore, Singapore.
authors.forename: Meera
authors.initials: M
authors.lastname: Gurumurthy
authors.affiliation: Tuberculosis Research Section, Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Ramandeep
authors.initials: R
authors.lastname: Singh
authors.affiliation: Novartis Institute for Tropical Diseases, Singapore, Singapore.
authors.forename: Thomas
authors.initials: T
authors.lastname: Dick
authors.affiliation: Novartis Institute for Tropical Diseases, Singapore, Singapore.
authors.forename: Francesca
authors.initials: F
authors.lastname: Blasco
authors.affiliation: Tuberculosis Research Section, Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Clifton E
authors.initials: CE
authors.lastname: Barry
authors.affiliation: Department of Pharmacy, National University of Singapore, Singapore, Singapore.
authors.forename: Paul C
authors.initials: PC
authors.lastname: Ho
authors.affiliation: Novartis Institute for Tropical Diseases, Singapore, Singapore.
authors.forename: Ujjini H
authors.initials: UH
authors.lastname: Manjunatha
mesh_terms: D000818:Animals; D018938:Caco-2 Cells; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D051379:Mice; D008826:Microbial Sensitivity Tests; D009169:Mycobacterium tuberculosis / Q000187:drug effects; D009593:Nitroimidazoles / Q000493:pharmacokinetics* / Q000494:pharmacology*; D012189:Retrospective Studies; D014376:Tuberculosis / Q000188:drug therapy*
chemical_list: D009593:Nitroimidazoles; C410767:pretomanid; C052587:4-nitroimidazole