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

TMC-207 (R207910)
TMC-207 is a diarylquinone discovered by Andries et al.
in 2005.
TMC207
Mechanism of Action. TMC-207 acts by targeting subunit c of the
ATP synthase of M. tuberculosis, leading to inhibition of the proton
pump activity of the ATP synthase (Andries et al., 2005; Koul et al.,
2007). Thus, the compound targets bacillary energy metabolism.
Antibacterial Activity. The TMC-207 MIC for M. tuberculosis is
0.03-0.12 mg/L. It has good activity against MAC, M. leprae, M. bovis,
M. marinum, M. kansasii, M. ulcerans, M. fortuitum, M. szulgai, and
M. abscessus (Andries et al., 2005; Huitric et al., 2007).
Bacterial Resistance. The proportion of M. tuberculosis mutants
resistant to four times the MIC is 5 × 10 −7 to 2 × 10 −8 . Resistance is
associated with two point mutations: D32V and A63P. This region of
the gene encodes the membrane-spanning domain of the ATP synthase
c subunit.
Absorption, Distribution, and Excretion. After oral ingestion of
400 mg of TMC-207, the t max
was 4 hours, the C max
was 5.5 mg/L
after 400 mg/day, and the AUC 0-24
was 65 mg·h/L. Based on these
data, the CL is ~6.2 L/h, although systemic clearance reportedly is
“triexponential.” Population pharmacokinetic studies have not been
published.
Pharmacokinetics, Efficacy, and Therapeutic Use. The anti-TB
activity of TMC-207 is correlated with time above MIC. In murine
TB, TMC-207 had superior bactericidal activity compared to isoniazid
and rifampin, and accelerated sterilization when combined with
rifampin, isoniazid, and pyrazinamide (Andries et al., 2005). In
patients with drug-susceptible TB, the rate of sputum bacillary decline
was similar to rifampin and isoniazid (Rustomjee et al., 2008a). A regimen
of TMC207 400 mg daily for 2 weeks followed by 200 mg three
times day thereafter was added to a background second-line regimen
of either kanamycin or amikacin, ofloxacin with or without ethambutol
in patients with TB resistant to both isoniazid and rifampin (MDR-
TB), and led to an 8-week sputum conversion of ~50% with TMC207
compared to 9% without (Diacon et al., 2009).
Untoward Effects. The adverse events encountered with TMC207
are mild and include nausea in 26% of patients and diarrhea in 13%
of patients, with others such as arthralgia, pain in extremities, and
hyperuricemia in a small proportion of patients (Diacon et al., 2009).
However, only a limited number of patients have been exposed to
this drug, so that the full side-effect profile is unclear.
PA-824
PA-824 is a nitroimidazopyran discovered by Stover
et al. in 2000.
PA-824
Mechanism of Action. PA-824 inhibits M. tuberculosis mycolic acid
and protein synthesis at the step between hydroxymycolate and ketomycolate
(Stover et al., 2000). Similar to the structurally related
metronidazole, PA-824 is a pro-drug that requires activation by the
bacteria via a nitro-reduction step that requires, among other factors,
a specific glucose-6-phosphate dehydrogenase, FGD1, and the
reduced deazaflavin co-factor F 420
(Bashiri et al., 2008). Another
mechanism involves generation of reactive nitrogen species such as
NO by PA-824’s des-nitro metabolite, which then augment the kill
of intracellular nonreplicating persistent bacilli by the innate immune
system (Singh et al., 2008).
Antibacterial Activity. In vitro, the drug kills both nonreplicating
M. tuberculosis that are under anaerobic conditions as well as
replicating bacteria in ambient air. The MICs of PA-824 against
M. tuberculosis range from 0.015–0.25 mg/L, but the drug lacks
activity against other mycobacteria.
Bacterial Resistance. The proportion of mutants resistant to 5 mg/L
of PA-824 is 10 -6 . Resistance arises due to changes in structure of
FGD, which is due to a variety of point mutations in fgd gene.
However, resistant isolates have also been identified that lack fgd
mutations, so that resistance may also be due to other mechanisms
(Stover et al., 2000).
Pharmacokinetics and Efficacy. In murine and guinea pig TB, PA-
824 was equivalent to standard doses of isoniazid (Stover et al.,
2000). In a recent murine TB study, 100 mg/kg/day of PA-824 with
pyrazinamide and rifampin showed total sterilization at 2 months
and no relapse, versus 15% relapse with the standard isoniazid,
rifampin, and pyrazinamide regimen (Tasneen et al., 2008). Phase 1
studies have been performed, but the pharmacokinetic data have not
been published. Phase 2 studies are in progress.
Ethionamide
Ethionamide (TRECATOR) is a congener of thioisonicotinamide.
ETHIONAMIDE
Mechanism of Action. Mycobacterial EthaA, an NADPH-specific,
FAD-containing monooxygenase, converts ethionamide to a sulfoxide,
and then to 2-ethyl-4-aminopyridine (Vannelli et al., 2002).
Although these products are not toxic to mycobacteria, it is believed
that a closely related and transient intermediate is the active antibiotic.
Ethionamide inhibits mycobacterial growth by inhibiting the
activity of the inhA gene product, the enoyl-ACP reductase of fatty
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CHAPTER 56
CHEMOTHERAPY OF TUBERCULOSIS, MYCOBACTERIUM AVIUM COMPLEX DISEASE, AND LEPROSY