pretomanid (Rx)

Incidence refers to use of pretomanid in combination with bedaquiline and linezolid

>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%)

<5%

• Gastrointestinal disorders: Pancreatitis, dysgeusia
• Laboratory investigations: Blood creatine phosphokinase increase, blood creatinine increase, blood alkaline phosphatase increase
• Blood and lymphatic system disorders: Leukopenia
• Metabolism and nutrition disorders: Hypomagnesemia, hyperglycemia, hypokalemia, hyperkalemia, hyponatremia
• Nervous system disorders: Dizziness, seizure

Contraindications

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

Cautions

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

Drug interaction overview

• 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

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

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

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

Absorption

Steady-state achieved: ~4-6 days

Peak plasma time

• Single-dose, fasting: 4 hr
• Single-dose, fed: 5 hr
• Steady-state: 4.5 hr

Peak plasma concentration

• Single-dose, fasting: 1.1 mcg/mL
• Single-dose, fed: 2 mcg/mL
• Steady-state: 1.7 mcg/mL

AUC

• Single-dose, fasting: 28.1-28.8 mcg⋅hr/mL
• Single-dose, fed: 51.6-53 mcg⋅hr/mL
• Steady-state: 30.2 mcg⋅hr/mL

Distribution

Protein bound: ~86.4%

Vd

• Single-dose, fasting: 180 L
• Single-dose, fed: 97 L

Metabolism

Metabolized by multiple reductive and oxidative pathways, with no single pathway considered as major

In vitro studies using recombinant CYP3A4 demonstrated that this enzyme is responsible for up to approximately 20% of the metabolism

Elimination

Half-life

• Single-dose, fasting: 16.9 hr
• Single-dose, fed: 17.4 hr
• Steady-state: 16 hr

Clearance

• Single-dose, fasting: 7.6 L/hr
• Single-dose, fed: 3.9 L/hr

Excretion

• Excreted primarily as metabolites
• Urine: 53%
• Feces: 38%

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

Missed dose

• Missed doses of the regimen for safety reasons: Can be made up at the end of treatment
• Doses of linezolid alone missed owing to linezolid adverse reactions should not be made up

Discontinuation

If either bedaquiline or pretomanid are discontinued, the entire combination regimen should also be discontinued

Linezolid permanently discontinued during initial 4 consecutive weeks: Bedaquiline and pretomanid should also be discontinued

Linezolid discontinued after initial 4 consecutive weeks: Continue administering bedaquiline and pretomanid

Storage

Store at room temperature <86ºF (30ºC)