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Pharmacokinetics and pharmacodynamics of clofazimine in the mouse model of tuberculosis.

Abstract

The anti-leprosy drug clofazimine has shown potential for shortening tuberculosis treatment; however, the current dosing of this 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 6 different clofazimine dosing regimens, including doses of 6.25, 12.5 and 25 mg/kg/day and 3 regimens with loading doses. Clofazimine progressively accumulated in the lungs, liver and spleen of mice, reaching levels greater than 50 μg/g in all tissues by 4 weeks of administration, while serum levels remained low at 1-2 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 anti-tuberculosis 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.

More information

Type
Journal Article
Author
Swanson RV
Adamson J
Moodley C
Ngcobo B
Ammerman N
Dorasamy A
Moodley S
Mgaga Z
Tapley A
Bester LA
Singh S
Grosset J
Almeida DV

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