Pretomanid

Indications

Pretomanid is used for: Indicated as part of a combination regimen with bedaquiline and linezolid for treatment of adults with pulmonary extensively drug-resistant (XDR) or treatment-intolerant or nonresponsive, multidrug-resistant (MDR) tuberculosis (TB)

Adult Dose

Tuberculosis Indicated as part of a combination regimen with bedaquiline and linezolid for treatment of adults with pulmonary extensively drug-resistant (XDR) or treatment-intolerant or nonresponsive multidrug-resistant (MDR) tuberculosis (TB) Dosage regimen Pretomanid 200 mg PO qDay x 26 weeks Bedaquiline 400 mg PO qDay x 2 weeks, THEN, 200 mg 3x/week with at least 48 hr between doses for x 24 weeks (total of 26 weeks) Linezolid 1200 mg PO qDay for 26 weeks; adjust dose as necessary (600 mg/day, further reduction to 300 mg/day, or interrupt dosing) for myelosuppression, peripheral neuropathy, or optic neuropathy

Child Dose

Renal Dose

Renal impairment: Effect on the safety, effectiveness, and pharmacokinetics unknown

Administration

Oral Administration Take with food Swallow tablet whole with water Must be used only in combination with bedaquiline and linezolid as part of the recommended dosing regimen Emphasize the need for compliance with the full course of therapy to patients Administer the combination regimen of pretomanid, bedaquiline, and linezolid by directly observed therapy

Contra Indications

Pretomanid is contraindicated in patients for whom bedaquiline and/or linezolid are contraindicated

Precautions

Hepatic adverse reactions were reported with the combination; interruption of treatment may be necessary; obtain ALT, AST, alkaline phosphatase, and bilirubin at a minimum at baseline, at 2 weeks, and then monthly Myelosuppression reported with combination (known adverse effect of linezolid); consider decreasing or interrupting linezolid dosing if patient has worsening myelosuppression Peripheral and optic neuropathy reported (known adverse effect of linezolid); interrupt linezolid if necessary QT prolongation reported with combination, although cardiac electrophysiology testing of pretomanid did not demonstrate prolonged QTc; discontinue if clinically significant ventricular arrhythmia or a QTcF interval of greater than 500 ms develops; if syncope occurs, obtain an ECG to detect QT prolongation Pretomanid caused testicular atrophy and impaired fertility in male rats; effects on human male fertility have not been fully evaluated Lactic acidosis reported with combination (known adverse effect of linezolid); immediately evaluate patient (including bicarbonate and lactic acid levels) if recurrent nausea or vomiting occurs; consider interrupting linezolid dosing or entire combination

Pregnancy-Lactation

Pregnancy No data are available on use in pregnant women Animal studies In animal reproduction studies, there was increased postimplantation loss in the presence of maternal toxicity (reduced bodyweight and feed consumption) with oral administration of pretomanid during organogenesis in rats at doses ~4 times the exposure at the recommended dose in humans No adverse embryofetal effects observed in rats or rabbits dosed with oral pretomanid during organogenesis at doses up to ~2 times the exposure in humans Clinical considerations Active TB in pregnancy associated with adverse maternal and neonatal outcomes, including maternal anemia, caesarean delivery, preterm birth, low birth weight, birth asphyxia, and perinatal infant death Infertility Males: Reduced fertility and testicular toxicity cannot be definitively ruled out as of August 2019 Lactation No data are available regarding the presence of pretomanid in human milk, or its effects on milk production or the breastfed infant Detected in rat milk; when a drug is present in animal milk, it is likely that the drug will be present in human milk Because of the potential for adverse reactions in nursing infants, the developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for the drug and any potential adverse effects on the breastfed infant

Interactions

Regimen associated with hepatotoxicity; avoid alcohol and hepatotoxic agents, including herbal supplements and drugs other than bedaquiline and linezolid Pretomanid may be in part metabolized by CYP3A4; avoid coadministration of strong or moderate CYP3A4 inducers In vitro studies demonstrated that pretomanid significantly inhibits OAT3; monitor for increased adverse effects and consider dosage reduction for OAT3 substrates

Adverse Effects

Side effects of Pretomanid : >10% Peripheral neuropathy (81%) Acne (39%) Anemia (37%) Nausea (37%) Vomiting (34%) Musculoskeletal pain (29%) Headache (28%) Transaminases increased (28%) Dyspepsia (24%) Decreased appetite (22%) Rash (21%) Pruritus (20%) Abdominal pain (19%) Pleuritic pain (19%) GGT increased (17%) Lower respiratory tract infection (15%) Hyperamylasemia (14%) Hemoptysis (13%) Cough (12%) Visual impairment (12%) Hypoglycemia (11%) 1-10% Abnormal weight loss (10%) Diarrhea (10%) Constipation (8%) Gastritis (8%) Neutropenia (8%) Dry skin (7%) Hypertension (7%) ECG QT prolonged (6%) Hyperlipasemia (6%) Insomnia (6%) Thrombocytopenia (6%)

Mechanism of Action

Nitroimidazooxazine antimycobacterial drug; kills actively replicating M tuberculosis by inhibiting mycolic acid biosynthesis, thereby blocking cell wall production Under anaerobic conditions, against nonreplicating 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 deazaflavin-dependent nitroreductase (Ddn), which is dependent on the reduced form of cofactor F420