Pretomanid

Pretomanide is available as nitroimidazo-oxazine with the molecular formula C14H12F3N3O5, a nitroimidazole prodrug for the treatment of tuberculosis. In order for the drug to develop its effect, pretomanide must be activated by a reduction of an aromatic nitro group. This is done via the coenzyme F420 of the tuberculosis pathogen Mycobacterium tuberculosis. Pretomanide was selected from 100 nitroimidazopyran derivatives. In preclinical studies, it did not prove to be the most effective agent, but the one with the best oral bioavailability.

Pretomanid may only be used in combination with bedaquiline (Sirturo®) and linezolid (Zyvoxid®) in patients with extremely resistant TB (XDR-TB) or in patients with multi-resistant TB (MDR-TB) who do not tolerate or do not respond to another therapy. The Nix TB study was relevant for approval, in which 109 patients were treated with Pretomanid in 3 clinics in South Africa. The patient characteristics and combination partners of Pretomanid were similar to those for which approval has now been granted. After 6 months of treatment and 6 months of follow-up, 95 of 107 patients (89 percent) were free of tuberculosis. The new combination therapy was thus significantly more successful than previous regimens for the treatment of XDR-TB. In 2 patients the therapy was extended to 9 months.

In 2019, the FDA approved Pretomanid for the treatment of highly resistant tuberculosis; it is only the third new antituberculosis drug to receive approval in over 50 years. The combination with bedaquiline and linezolid is expected to shorten the duration of treatment for extremely resistant TB (XDR-TB) and increase the cure rate (Ignatius EH et al. 2019). Currently, the cure rate for XDR-B is only 34%. For comparison: In studies the triple therapy of Pretomanid, Bedaquiline and Linezolid showed healing rates of 89% (Dheda K et al. 2019). Marketing authorisation holder is the TB Alliance - a non-profit product development partnership.

Pretomanide is used orally in combination with bedaquiline and linezolid in adults for the treatment of extremely resistant tuberculosis or in the event of intolerance to tuberculosis treatment or failure to respond to therapy for multidrug-resistant pulmonary tuberculosis (Bahuguna A et al. 2020). The following dosages and therapy times are planned:

• Pretomanid 200 mg once daily orally for 26 weeks
• Bedaquiline 400 mg once daily orally for two weeks, then 200 mg orally three times a week for 24 weeks (interval between doses at least 48 hours)
• Linezolid 1200 mg daily orally for 26 weeks with dose adjustments for known linezolid toxicity.

The most common side effects include neurogenic damage, acne, nausea, headaches, hypoglycemia, diarrhea, liver damage.

Pretomanid was not approved by a single pharmaceutical company, but by the non-profit organization "TB Alliance". The TB Alliance is an organization that brings together governments and private donors, research institutes and pharmaceutical companies that want to accelerate the development of and access to new tuberculosis drugs.

The FDA had processed the application for approval of Pretomanid under the newly established LPAD (Limited Population Pathway for Antibacterial and Antifungal Drugs) procedure and under priority and orphan drug status.

1. TB Alliance htt status ps://www.tballiance.org/portfolio/compound/pretomanid
2. Bahuguna A et al (2020) An overview of new antitubercular drugs, drug candidates, and their targets. Med Res Rev 40:263-292.
3. Dheda K et al (2019) The Lancet Respiratory Medicine Commission: 2019 update: epidemiology, pathogenesis, transmission, diagnosis, and management of multidrug-resistant and incurable tuberculosis. Lancet Respir Med 7:820-826.
4. Ignatius EH et al (2019) New Drugs for the Treatment of Tuberculosis. Clin Chest Med 40: 811-827.
5. Srivastava S et al. (2019) Duration of pretomanid/moxifloxacin/pyrazinamide therapy compared with standard therapy based on time-to-extinction mathematics. J Antimicrob Chemother doi: 10.1093/jac/dkz460
6. Tweed CD et al (2019) Bedaquiline, moxifloxacin, pretomanid, and pyrazinamide during the first 8 weeks of treatment of patients with drug-susceptible or drug-resistant pulmonary tuberculosis: a multicentre, open-label, partially randomised, phase 2b trial. Lancet Respir Med 7:1048-1058.