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.