DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

1560 Clofazimine
Clofazimine (LAMPRENE) is a fat-soluble riminophenazine
dye. It was discontinued in 2005 but remains licensed as
an orphan drug.
SECTION VII
CHEMOTHERAPY OF MICROBIAL DISEASES
CLOFAZIMINE
Mechanism of Action. The biochemical basis for the antimicrobial
actions of clofazimine remains to be established (Anonymous,
2008a). Possible mechanisms of action include:
• membrane disruption
• inhibition of mycobacterial phospholipase A 2
• inhibition of microbial K + transport
• generation of hydrogen peroxide
• interference with the bacterial electron transport chain
However, it is known that clofazimine has both antibacterial
activity as well as anti-inflammatory effects via inhibition of
macrophages, T cells, neutrophils, and complement.
Antibacterial Activity. The MICs for M. avium clinical isolates are
1-5 mg/L. The MICs for M. tuberculosis are ~1.0 mg/L. The compound
also is useful for treatment of chronic skin ulcers (Buruli ulcer) produced
by Mycobacterium ulcerans. It has activity against many
gram-positive bacteria with an MIC ≤1.0 mg/L against S. aureus,
coagulase-negative Staphylococci, Streptococcus pyogenes, and
Listeria monocytogenes. Gram-negative bacteria have MICs >32 mg/L.
Bacterial Resistance. Mechanisms of resistance are unknown.
Absorption, Distribution, and Excretion. Clofazimine’s oral
bioavailability is highly variable, 45-60%; bioavailability is
increased 2-fold by high-fat meals and decreased 30% by antacids
(Nix et al., 2004). After a single dose, clofazimine is best modeled
using a one-compartment model and has a prolonged absorption
phase; after 200 mg of clofazimine, the t max
is 5.3-7.8 hours. After
prolonged repeated dosing , the t 1/2
is ~70 days. For PK data, see
Table 56–2 and Nix et al. (2004). As a result of the good penetration
into many tissues, a reddish black discoloration of skin and body
secretions may occur and take a long time to resolve. Crystalline
deposits of the drug have been encountered in many tissues at
autopsy (Anonymous, 2008a). Clofazimine is metabolized in the
liver in four steps: hydrolytic dehalogenation, hydrolytic deamination,
glucuronidation, and hydroxylation.
Dosing. Clofazimine is administered orally at doses up to 300 mg
a day.
Untoward Effects. GI problems are encountered in 40-50% of
patients and include abdominal pain, diarrhea, nausea, and vomiting.
In patients who have died following the abdominal pain, crystal deposition
in intestinal mucosa, liver, spleen, and abdominal lymph
nodes has been demonstrated (Anonymous, 2008a). Body secretion
discoloration, eye discoloration, and skin discoloration occur in most
patients and can lead to depression in some patients.
Drug interactions. Anti-inflammatory effects may be inhibited by
dapsone.
Fluoroquinolones
Fluoroquinolones are DNA gyrase inhibitors. Their chemistry, spectrum
of activity, pharmacology, and adverse events are discussed in
greater detail in Chapter 52. Drugs such as ofloxacin and
ciprofloxacin have been second-line anti-TB agents for many years,
but they are limited by the rapid development of resistance. Adding
C8 halogen and C8 methoxy groups markedly reduces the propensity
for drug resistance. Of the C8 methoxy quinolones, moxifloxacin
(approved by the Food and Drug Administration for
nontubercular infections) is furthest along in clinical testing as an
anti-TB agent. Moxifloxacin is being studied to replace either isoniazid
or ethambutol.
Microbial Pharmacokinetics-Pharmacodynamics Relevant to TB.
Fluoroquinolone microbial kill is best explained by AUC 0-24
/MIC
ratio. In preclinical models, moxifloxacin AUC 0-24
/MIC exposures
equivalent to those from the standard 400-mg dose were associated
with good microbial kill but amplified the drug-resistant subpopulation,
so that resistance emerged in 7-13 days with monotherapy
(Gumbo et al., 2004). This time to emergence of resistance harmonizes
well with speed of resistance emergence in patients (Ginsburg et al.,
2003). Moxifloxacin exposure best associated with minimizing emergence
of resistance was an AUC 0-24
/MIC of 53. Clinical trial simulations
revealed that doses >400 mg a day might better achieve this
AUC/MIC, which experiments in mice substantiate (Almeida et al.,
2007). Given that rifamycins reduce moxifloxacin AUC, these results
point to a potential concern of quinolone resistance. Unfortunately,
the safety of moxifloxacin doses >400 mg has not been established.
Therapeutic Uses in Treatment of TB. In TB patients, moxifloxacin
(400 mg/day) has bactericidal effects similar to that of standard doses
of isoniazid (Johnson et al., 2006). When replacing ethambutol in
the standard multi-drug regimen, 400 mg/day of moxifloxacin produces
faster sputum conversion at 4 weeks than ethambutol (Burman
et al., 2006b). In a comparison study of moxifloxacin, gatifloxacin,
ofloxacin, and ethambutol as the fourth drug administered concurrently
with isoniazid, rifampin, and pyrazinamide (Rustomjee et al.,
2008b), moxifloxacin led to faster rates of bacterial kill during the
early phases, gatifloxacin was equivalent by the eighth week, and
ofloxacin was no better than ethambutol. Moxifloxacin is currently
being studied in a phase 3 trial that may eventually lead to 4-month
duration of anti-TB therapy compared to the current 6 months.
Drug Interactions Relevant to TB. In a study of volunteers treated
with rifampin, moxifloxacin, or both drugs, rifampin reduced the
moxifloxacin AUC 0-24
by 27% via induction of sulfate conjugation
(Weiner et al., 2007). In another study, rifapentine reduced moxifloxacin
AUC 0-24
by 17% (Dooley et al., 2008). These studies suggest
that the most important cause of pharmacokinetic variability for
moxifloxacin is concomitantly administered drugs for tuberculosis.