PRETOMANID

Clinical safety rating: caution

Comprehensive clinical and safety monograph for PRETOMANID (PRETOMANID).

How it works

Prodrug that is activated by mycobacterial nitroreductase (Ddn) to form reactive intermediates that inhibit mycolic acid synthesis and kill non-replicating M. tuberculosis.

What the body does with it

Metabolism	Primarily hydrolyzed by serum albumin to form an inactive metabolite; also metabolized via CYP3A4 and conjugation.
Excretion	Primarily metabolized; renal excretion of unchanged drug accounts for <1% of dose; fecal excretion is minimal. The main route of elimination is via metabolism, with metabolites excreted in urine (approximately 38-50% of total radioactivity) and feces (approximately 38-50%).
Half-life	Terminal elimination half-life is approximately 17-20 hours (range 14-28 hours) in patients with drug-susceptible TB; context: supports once-daily dosing, but requires monitoring for QT prolongation.
Protein binding	Approximately 86-91% bound to human plasma proteins, primarily to albumin.
Volume of Distribution	Apparent volume of distribution is approximately 320-580 L (or ~4-7 L/kg for a 70 kg person), indicating extensive tissue distribution.
Bioavailability	Oral: >70% under fed conditions; high-fat meal increases absorption (Cmax and AUC increased ~2-fold compared to fasting), thus recommended to take with food.
Onset of Action	Oral: Time to maximal concentration (Tmax) is 4-6 hours; clinical antimycobacterial effect is expected within days, but bactericidal activity begins after a lag period of 1-2 days in vitro.
Duration of Action	Duration of bactericidal effect is sustained over the 24-hour dosing interval; clinical notes: used in combination regimens for multidrug-resistant tuberculosis (MDR-TB) with a recommended duration of 6 months in the Nix-TB regimen.

Classification & Brands

Dosing & administration

400 mg orally once daily for 26 weeks, administered with food.

Dosage form	TABLET
Renal impairment	No dose adjustment required for mild to moderate renal impairment (CrCl ≥30 mL/min). Safety and efficacy not established in severe renal impairment (CrCl <30 mL/min) or ESRD; use with caution.
Liver impairment	Child-Pugh Class A: No adjustment. Child-Pugh Class B: Use with caution; no specific dose recommendation. Child-Pugh Class C: Contraindicated.
Pediatric use	Safety and efficacy not established in pediatric patients (age <18 years); clinical trials ongoing, no weight-based dosing recommended.
Geriatric use	No specific dose adjustment; clinical studies included limited patients aged ≥65 years; use with caution due to potential age-related renal and hepatic function decline.

Use during pregnancy

1st trimester	Consult provider
2nd trimester	Consult provider
3rd trimester	Consult provider

Clinical note

Comprehensive clinical and safety monograph for PRETOMANID (PRETOMANID).

Breastfeeding	No data on human milk excretion. In lactating rats, pretomanid and metabolites are excreted in milk. M/P ratio unknown. Due to potential for adverse reactions in nursing infants, advise against breastfeeding during therapy.
Teratogenic Risk	In animal studies, pretomanid caused embryotoxicity and teratogenicity (skeletal and soft tissue malformations) at exposures similar to human therapeutic levels. No human pregnancy data exist. Use only if benefit outweighs risk; avoid in first trimester if possible.

Warnings & precautions

■ FDA Black Box Warning

WARNING: Hepatotoxicity; monitor liver function tests closely. Not recommended in patients with severe hepatic impairment.

Side Effect Profile

Serious Effects

Absolute Contraindications

["Known hypersensitivity to pretomanid or any component","Severe hepatic impairment (Child-Pugh C)","Concomitant use with strong CYP3A4 inducers/rifamycins"]

Clinical Precautions

Precautions

["Hepatotoxicity, including liver failure and death","QT interval prolongation","Increased risk of myelosuppression with concurrent chemotherapeutic agents","Fetal harm (pregnancy category C)","Potential for optic and peripheral neuropathy"]

Clinical Tips & Counseling

Drug interactions

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PRETOMANID

Clinical safety rating: caution

Comprehensive clinical and safety monograph for PRETOMANID (PRETOMANID).

How it works

Prodrug that is activated by mycobacterial nitroreductase (Ddn) to form reactive intermediates that inhibit mycolic acid synthesis and kill non-replicating M. tuberculosis.

What the body does with it

Metabolism	Primarily hydrolyzed by serum albumin to form an inactive metabolite; also metabolized via CYP3A4 and conjugation.
Excretion	Primarily metabolized; renal excretion of unchanged drug accounts for <1% of dose; fecal excretion is minimal. The main route of elimination is via metabolism, with metabolites excreted in urine (approximately 38-50% of total radioactivity) and feces (approximately 38-50%).
Half-life	Terminal elimination half-life is approximately 17-20 hours (range 14-28 hours) in patients with drug-susceptible TB; context: supports once-daily dosing, but requires monitoring for QT prolongation.
Protein binding	Approximately 86-91% bound to human plasma proteins, primarily to albumin.
Volume of Distribution	Apparent volume of distribution is approximately 320-580 L (or ~4-7 L/kg for a 70 kg person), indicating extensive tissue distribution.
Bioavailability	Oral: >70% under fed conditions; high-fat meal increases absorption (Cmax and AUC increased ~2-fold compared to fasting), thus recommended to take with food.
Onset of Action	Oral: Time to maximal concentration (Tmax) is 4-6 hours; clinical antimycobacterial effect is expected within days, but bactericidal activity begins after a lag period of 1-2 days in vitro.
Duration of Action	Duration of bactericidal effect is sustained over the 24-hour dosing interval; clinical notes: used in combination regimens for multidrug-resistant tuberculosis (MDR-TB) with a recommended duration of 6 months in the Nix-TB regimen.

Classification & Brands

Dosing & administration

400 mg orally once daily for 26 weeks, administered with food.

Dosage form	TABLET
Renal impairment	No dose adjustment required for mild to moderate renal impairment (CrCl ≥30 mL/min). Safety and efficacy not established in severe renal impairment (CrCl <30 mL/min) or ESRD; use with caution.
Liver impairment	Child-Pugh Class A: No adjustment. Child-Pugh Class B: Use with caution; no specific dose recommendation. Child-Pugh Class C: Contraindicated.
Pediatric use	Safety and efficacy not established in pediatric patients (age <18 years); clinical trials ongoing, no weight-based dosing recommended.
Geriatric use	No specific dose adjustment; clinical studies included limited patients aged ≥65 years; use with caution due to potential age-related renal and hepatic function decline.

Use during pregnancy

1st trimester	Consult provider
2nd trimester	Consult provider
3rd trimester	Consult provider

Clinical note

Comprehensive clinical and safety monograph for PRETOMANID (PRETOMANID).

Breastfeeding	No data on human milk excretion. In lactating rats, pretomanid and metabolites are excreted in milk. M/P ratio unknown. Due to potential for adverse reactions in nursing infants, advise against breastfeeding during therapy.
Teratogenic Risk	In animal studies, pretomanid caused embryotoxicity and teratogenicity (skeletal and soft tissue malformations) at exposures similar to human therapeutic levels. No human pregnancy data exist. Use only if benefit outweighs risk; avoid in first trimester if possible.

Warnings & precautions

■ FDA Black Box Warning

WARNING: Hepatotoxicity; monitor liver function tests closely. Not recommended in patients with severe hepatic impairment.

Side Effect Profile

Serious Effects

Absolute Contraindications

["Known hypersensitivity to pretomanid or any component","Severe hepatic impairment (Child-Pugh C)","Concomitant use with strong CYP3A4 inducers/rifamycins"]