Source: Health Products Regulatory Authority (ZA) Revision Year: 2022 Publisher: Novartis South Africa (Pty) Ltd, Magwa Crescent West, Jukskei View, Waterfall City, Johannesburg, 2090
Pharmacotherapeutic group, ATC: Drugs for the treatment of lepra, J04BA01
Clofazimine is thought to exert its anti-mycobacterial effect through multiple mechanisms. The primary mechanism of action for the antimicrobial activity of clofazimine can be postulated through its membranedirected activity, including the bacterial respiratory chain and ion transporters. Intracellular redox cycling, involving oxidation of reduced clofazimine, leads to the generation of antimycobacterial reactive oxygen species (ROS), superoxide-hydrogen peroxide (H2O2).
Secondly, interaction of clofazimine with membrane phospholipids results in the generation of antimycobacterial lysophospholipids, which promote membrane dysfunction, resulting in interference with K+ uptake. Both mechanisms result in interference with cellular energy metabolism by disrupting ATP production.
The third proposed mechanism of action is binding preferentially to mycobacterial deoxyribonucleic acid (DNA) with particular affinity to guanine bases and inhibiting mycobacterial replication and growth. Clofazimine also displays an anti-inflammatory effect, which may contribute to the effect of clofazimine in controlling erythema nodosum leprosum (ENL) reactions.
Anti-inflammatory activity of clofazimine is primarily through inhibition of T lymphocyte activation and proliferation. Clofazimine may indirectly interfere with the proliferation of T cells by promoting the release of ROS and E-series prostaglandins (PGs), especially PGE2 from neutrophils and monocytes.
Clofazimine may also exert anti-mycobacterial activity by its effect on tissue macrophages. Clofazimine has a tendency to concentrate selectively in cells of the reticuloendothelial system. Clofazimine has shown apoptosis inducing properties in activated macrophages. Clofazimine has been shown to inhibit MtSerB2, a phosphatase produced by M. tuberculosis that is believed to help the pathogen to evade the host’s immune response.
Clofazimine exerts a mycobacteriostatic and weakly mycobactericidal effect on Mycobacterium leprae. Clofazimine appears to bind preferentially to mycobacterial DNA and inhibit mycobacterial replication and growth.
The minimum inhibitory concentration of clofazimine for M. leprae in mouse tissue has been estimated at between 0.1 and 1 microgram per gram; uneven tissue distribution precludes a more accurate estimate. The onset of antimicrobial activity of clofazamine is slow, and can only be demonstrated after about 50 days of therapy.
No cross-resistance occurs with dapsone and rifampicin, probably because clofazimine has a different mode of action. M. leprae resistant to clofazimine have been reported in isolated cases.
The MIC of clofazimine against drug susceptible as well as single drug-resistant, multidrug-resistant and extensively drug resistant TB strains ranges from <0.0625 μg/mL to >1 μg/mL. The majority [84.7% (95% CI: 69.5%, 93.1%)] of the tested strains have a reported MIC value of ≤0.5 μg/mL for clofazimine. Clofazimine does not show cross-resistance with isoniazid or rifampin. In vitro resistance to clofazimine in mycobacterium tuberculosis has been mapped to mutations in the transcriptional regulator Rv0678 which results in the upregulation of MmpS5-MmpL5, an efflux pump. These mutants show cross-resistance to bedaquiline. Two additional mutations (Rv1979c and Rv2535c) have also been associated with clofazimine resistance in vitro; however, the mechanism and clinical relevance of these mutations is yet to be determined.
Clofazimine is absorbed slowly. Bioavailability of the micronised suspension in an oil-wax base is up to 70% after a 100 mg dose and decreases with higher doses.
The time to reach peak plasma concentration (median time) of clofazimine decreases from 12 to 8 hours under fed conditions relative to the fasted state. Administration of the medicine with food increases its bioavailability in terms of AUC (area under the concentration-time curve) by about 60%, and tends to accelerate the absorption rate.
After administration of a single oral dose of 200 mg clofazimine with a morning meal, mean (±SD) peak plasma concentrations of 0.41 (±0.14) micrograms per mL (861 (±289) pmol/g) were measured in healthy volunteers. When clofazimine is taken on an empty stomach, the peak plasma concentration was approximately 20% lower.
After repeated administration of clofazimine to leprosy patients in daily doses of 50 mg and 100 mg, mean trough concentrations of 0.27 and 0.43 micrograms/mL (580 pmol/g and 910 pmol/g), respectively, were measured after 42 consecutive days when concentrations were still increasing. The time to achieve steady state concentration has not been studied. From modelling studies, steady state concentrations were not reached after 20 weeks of treatment. The accumulation ratios after 50 and 100 mg daily doses of clofazimine on day 42 were 9.88 and 11.61, respectively.
Clofazimine is strongly lipophilic and accumulates chiefly in fatty tissue and in the macrophages of the reticuloendothelial system. After long-term treatment, clofazimine was detectable as crystals particularly in the following organs, tissues and body fluids: subcutaneous fat, mesenteric lymph nodes, bile, gall bladder, adrenals, spleen, small intestine, liver, muscle tissue, bones and skin. Clofazimine does not appear to cross the intact blood-brain barrier.
Clofazimine crosses the placenta and passes into breast milk in sufficient quantities to cause discolouration of the milk.
Clofazimine bound to the alpha- and beta-lipoproteins in serum, particularly the beta-lipoproteins, and the binding was saturable at approximately 10 microgram/mL (21141 pmol/g) concentrations. Binding to gamma-globulin and albumin was negligible.
Information on the metabolism of clofazimine is limited. Three metabolites, two of which are glucuronides, have been identified in urine.
Clofazimine is eliminated very slowly from the plasma. The mean elimination half-life of unchanged substance following a single dose of 200 mg in healthy volunteers was 10.6 (±4.0) days. After repeated administration of 50 mg and 100 mg daily to leprosy patients, the elimination half-life was about 25 days. Unchanged clofazimine is excreted via the bile mainly in the faeces. Within 3 days on average, 35% of the dose is recovered in faeces. No more than 0.4% of the dose is found in the urine as unchanged clofazimine after 24 hours. Urinary metabolites account for about 0.6% of the daily dose. However, clofazimine could still be detected in faeces several months after discontinuation of treatment.
No data is available on the effects of renal or hepatic dysfunction, or of age, on the pharmacokinetics of clofazimine.
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