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General Information

Pretomanid is a nitroimidazooxazine antimycobacterial drug.

Pretomanid is specifically indicated as part of a combination regimen with bedaquiline and linezolid for the treatment of adults with pulmonary extensively drug resistant (XDR) or treatment-intolerant or nonresponsive multidrug-resistant (MDR) tuberculosis (TB).

Pretomanid is supplied as a tablet for oral administration. Pretomanid Tablets must be administered in combination with bedaquiline and linezolid. The recommended dosage and duration for bedaquiline and linezolid when used in the combination regimen with Pretomanid Tablet are as follows:

• Pretomanid Tablet 200 mg orally (1 tablet of 200 mg), once daily, for 26 weeks. Swallow Pretomanid Tablets whole with water.

• Bedaquiline 400 mg orally once daily for 2 weeks followed by 200 mg 3 times per week, with at least 48 hours between doses, for 24 weeks for a total of 26 weeks

• Linezolid starting at 1,200 mg orally per day for 26 weeks, with dose adjustments to 600 mg daily and further reduction to 300 mg daily or interruption of dosing as necessary for known linezolid adverse reactions of myelosuppression, peripheral neuropathy, and optic neuropathy.

Take the combination regimen of Pretomanid Tablets, bedaquiline, and linezolid with food. If the combination regimen of Pretomanid Tablets, bedaquiline, and linezolid is interrupted by a healthcare provider for safety reasons, missed doses can be made up at the end of the treatment; doses of linezolid alone missed due to linezolid adverse reactions should not be made up. Dosing of the combination regimen of Pretomanid Tablets, bedaquiline, and linezolid can be extended beyond 26 weeks, if necessary.

Clinical Results

FDA Approval

The Nix-TB trial was an open-label study conducted in three centers in South Africa in patients with XDR, treatment-intolerant MDR, or non-responsive MDR pulmonary TB. The patients received a combination regimen of Pretomanid Tablets, bedaquiline, and linezolid for 6 months (extended to 9 months in 2 patients) with 24 months of follow-up; linezolid starting dose was either 600 mg twice daily or 1200 mg once daily. One hundred seven of the 109 patients enrolled were assessable for the primary efficacy analyses with two patients remaining in follow-up for the primary outcome assessment. Treatment failure was defined as the incidence of bacteriologic failure (reinfection – culture conversion to positive status with different M. tuberculosis strain), bacteriological relapse (culture conversion to positive status with same M. tuberculosis strain), or clinical failure through follow-up until 6 months after the end of treatment. Of the 107 patients assessed, outcomes were classified as success for 95 (89%) patients and failure for 12 (11%) patients.

Side Effects

Adverse reactions associated with the use of Pretomanid may include, but are not limited to, the following:

peripheral neuropathy

acne

anemia

nausea

vomiting

headache

increased transaminases

dyspepsia

decreased appetite

rash

pruritus

abdominal pain

pleuritic pain

increased gamma-glutamyltransferase

lower respiratory tract infection

hyperamylasemia

hemoptysis

back pain

cough

visual impairment

hypoglycemia

abnormal loss of weight

diarrhea

Mechanism of Action

Pretomanid is a nitroimidazooxazine antimycobacterial drug. Pretomanid kills actively replicating M. tuberculosis by inhibiting mycolic acid biosynthesis, thereby blocking cell wall production. Under anaerobic conditions, against non-replicating bacteria, pretomanid acts as a respiratory poison following nitric oxide release. All of these activities require nitro-reduction of pretomanid within the mycobacterial cell by the deazaflavin-dependent nitroreductase, Ddn, which is dependent on the reduced form of the cofactor F420. Reduction of F420 is accomplished by the F420-dependent glucose-6-phosphate dehydrogenase.