7.2 Composition and duration of the regimen

The BPaL regimen comprises three components – bedaquiline, pretomanid and linezolid – that are used as a package. Bedaquiline and linezolid are used in longer regimens (see Section 6.2) and bedaquiline is also used in the shorter all-oral regimen (see Section 5).

Pretomanid is a new medicine, and its safety and effectiveness have not been established for its use in combination with medicines other than bedaquiline and linezolid as part of the BPaL regimen (96, 97). Pretomanid is a nitroimidazole (i.e. in the same chemical class as delamanid) and is a prodrug that is metabolically activated by a nitroreductase, producing various metabolites that are responsible for its therapeutic action. Pretomanid inhibits cell wall biosynthesis and, under anaerobic conditions, it causes respiratory poisoning of the bacterial cell through the release of reactive nitrogen species. Pretomanid possesses activity in both replicating and non-replicating M. tuberculosis bacilli (AbdelRahman SM. unpublished data, Children’s Mercy Hospital, Kansas City, United States of America, November 2019). In vitro, preclinical and clinical data support a role for pretomanid as part of the BPaL regimen. Because there is no experience of the use of this medicine in other combinations, pretomanid is not currently recommended for use outside the context of the BPaL regimen. Pretomanid is currently being further tested as part of combination regimens for the treatment of both drugsusceptible and drug-resistant TB.¹⁶ The most common adverse reactions observed in patients treated with pretomanid in combination with bedaquiline and linezolid included damage to the nerves (peripheral neuropathy), acneiform dermatitis, anaemia, nausea, vomiting, headache, increased liver enzymes (transaminases and gamma-glutamyltransferase), indigestion (dyspepsia), rash, pruritus, increased pancreatic enzymes (hyperamylasemia), decreased appetite, increased transaminases and gamma glutamyl transpeptidase, visual impairment, low blood sugar (hypoglycemia), abdominal pain, musculoskeletal pain and diarrhoea (96, 97). Data from the animal model study also suggested the side-effect of infertility related to pretomanid (Abdel-Rahman SM. unpublished data, Children’s Mercy Hospital, Kansas City, United States of America, November 2019) (96). The WHO GDG (November 2019) highlighted the potential difficulties in monitoring of infertility in a programmatic setting. Additional human sperm studies recommended by the United States Food and Drug Administration (US FDA) are being carried out by TB Alliance; however, the findings were not available at the time of the GDG meeting (1). Infertility is a serious issue because it affects both patients and their families; given this potential side-effect, the balance of the desirable and undesirable effects of the treatment needs to be carefully discussed with the patient, who should be involved in the treatment decision.

The BPaL regimen comprised pretomanid administered at 200 mg once daily, bedaquiline administered at 400 mg once daily for the first 2 weeks of treatment (days 1–14) and then 200 mg three times a week thereafter, and linezolid at 1200 mg per day.

drugs for adults and adolescents

Dose modifications for bedaquiline and pretomanid are not allowed. Linezolid high dose (1200 mg once daily) in the BPaL regimen can be reduced after the first month of treatment in patients with linezolid-induced peripheral neuropathy or myelosuppression.

Following the regimen used in the Nix-TB study, the linezolid dosage is 1200 mg per day. At the time the study commenced, all study participants first received 600 mg of linezolid twice a day because that was the approved dose used to treat bacterial infections for up to 28 days at the time. However, in May 2018, the protocol was changed to dosing of 1200 mg of linezolid once a day. Dose reduction to 600 mg daily and further to 300 mg daily or temporary cessation of linezolid was permitted for up to 35 consecutive days for any known linezolid adverse reactions of myelosuppression, peripheral neuropathy and optic neuropathy. If toxicity prohibited further treatment with linezolid, then patients could remain on bedaquiline and pretomanid provided that they had received the 1200 mg per day dose for at least the first 4 consecutive weeks, were sputum smear negative or had only trace or scanty results, and were responding to treatment based on clinical monitoring and follow-up.17 Missed doses of linezolid were not made up during the Nix-TB study, and dose modifications for bedaquiline and pretomanid were not allowed (1, 95).

With the experience of linezolid use in the Nix-TB study, the following modifications of linezolid dosing in the management of adverse events may be considered for the BPaL regimen:

• Linezolid can be temporarily interrupted, or the dosage can be reduced after the first month.

• The dose of linezolid can be reduced from 1200 mg once daily to 600 mg or 300 mg once daily.

The BPaL regimen is given for a duration of 6–9 months. The standard treatment duration is 6 months. If the sputum culture taken after 4 months of treatment is positive, patients can receive an additional 3 months of treatment (total 9 months). The full BPaL regimen can be temporarily interrupted for a maximum of 35 consecutive days. Any missed days will be made up by extending the duration of the regimen by the number of days missed, but this must not be more than 35 days.

¹⁶ A Phase III trial (called SimpliciTB) of BPaMZ, targeting patients with drug-susceptible TB or MDR-TB, is being implemented. The primary end-point is culture conversion at 2 months, with a secondary end-point of cure 6 months after completion of therapy. A previous Phase IIb study of this BPaMZ regimen showed almost 100% culture conversion at 2 months in patients with MDR-TB. ZeNix, a follow-on trial of Nix-TB, is exploring lower doses and shorter durations of linezolid within Nix-TB to minimize toxicity.

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