title: Pharmacokinetics and pharmacodynamics of clofazimine in a mouse model of tuberculosis.
abstract: The antileprosy drug clofazimine has shown potential for shortening tuberculosis treatment; however, the current dosing of the drug is not evidence based, and the optimal dosing is unknown. Our objective was to conduct a preclinical evaluation of the pharmacokinetics and pharmacodynamics of clofazimine in the mouse model of tuberculosis, with the goal of providing useful information on dosing for future studies. Pharmacokinetic parameters were evaluated in infected and uninfected BALB/c mice. Pharmacodynamic parameters were evaluated in Mycobacterium tuberculosis-infected mice that were treated for 12 weeks with one of six different clofazimine dosing regimens, i.e., doses of 6.25, 12.5, and 25 mg/kg of body weight/day and 3 regimens with loading doses. Clofazimine progressively accumulated in the lungs, livers, and spleens of the mice, reaching levels of greater than 50 μg/g in all tissues by 4 weeks of administration, while serum drug levels remained low at 1 to 2 μg/ml. Elimination of clofazimine was extremely slow, and the half-life was dependent on the duration of drug administration. Clofazimine exhibited dose-dependent tissue and serum concentrations. At any dose, clofazimine did not have bactericidal activity during the first 2 weeks of administration but subsequently demonstrated potent, dose-independent bactericidal activity. The antituberculosis activity of clofazimine was dependent on neither the dose administered nor the drug concentrations in the tissues, suggesting that much lower doses could be effectively used for tuberculosis treatment.
authors.affiliation: KwaZulu-Natal Research Institute for Tuberculosis and HIV, Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa School of Laboratory Medicine and Medical Sciences, College of Health Sciences, University of KwaZulu-Natal, Durban, South Africa.
authors.forename: Rosemary V
authors.initials: RV
authors.lastname: Swanson
authors.affiliation: KwaZulu-Natal Research Institute for Tuberculosis and HIV, Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa.
authors.forename: John
authors.initials: J
authors.lastname: Adamson
authors.affiliation: KwaZulu-Natal Research Institute for Tuberculosis and HIV, Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa.
authors.forename: Chivonne
authors.initials: C
authors.lastname: Moodley
authors.affiliation: KwaZulu-Natal Research Institute for Tuberculosis and HIV, Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa.
authors.forename: Bongani
authors.initials: B
authors.lastname: Ngcobo
authors.affiliation: KwaZulu-Natal Research Institute for Tuberculosis and HIV, Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa Johns Hopkins Center for Tuberculosis Research, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Nicole C
authors.initials: NC
authors.lastname: Ammerman
authors.affiliation: KwaZulu-Natal Research Institute for Tuberculosis and HIV, Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa.
authors.forename: Afton
authors.initials: A
authors.lastname: Dorasamy
authors.affiliation: KwaZulu-Natal Research Institute for Tuberculosis and HIV, Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa.
authors.forename: Sashen
authors.initials: S
authors.lastname: Moodley
authors.affiliation: KwaZulu-Natal Research Institute for Tuberculosis and HIV, Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa.
authors.forename: Zinhle
authors.initials: Z
authors.lastname: Mgaga
authors.affiliation: KwaZulu-Natal Research Institute for Tuberculosis and HIV, Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa University of California, San Francisco, School of Medicine, San Francisco, California, USA Howard Hughes Medical Institute, Chevy Chase, Maryland, USA.
authors.forename: Asa
authors.initials: A
authors.lastname: Tapley
authors.affiliation: Biomedical Resources Unit, College of Health Sciences, University of KwaZulu-Natal, Westville, South Africa.
authors.forename: Linda A
authors.initials: LA
authors.lastname: Bester
authors.affiliation: Biomedical Resources Unit, College of Health Sciences, University of KwaZulu-Natal, Westville, South Africa.
authors.forename: Sanil
authors.initials: S
authors.lastname: Singh
authors.affiliation: KwaZulu-Natal Research Institute for Tuberculosis and HIV, Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa Johns Hopkins Center for Tuberculosis Research, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Jacques H
authors.initials: JH
authors.lastname: Grosset
authors.affiliation: KwaZulu-Natal Research Institute for Tuberculosis and HIV, Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa Johns Hopkins Center for Tuberculosis Research, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA dalmeid3@jhmi.edu.
authors.forename: Deepak V
authors.initials: DV
authors.lastname: Almeida
mesh_terms: D000818:Animals; D000995:Antitubercular Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use; D002853:Chromatography, Liquid; D002991:Clofazimine / Q000493:pharmacokinetics* / Q000627:therapeutic use; D005260:Female; D013058:Mass Spectrometry; D051379:Mice; D008807:Mice, Inbred BALB C; D011485:Protein Binding; D014376:Tuberculosis / Q000097:blood* / Q000188:drug therapy*
chemical_list: D000995:Antitubercular Agents; D002991:Clofazimine