Chemical formula: C₁₄H₁₂F₃N₃O₅ Molecular mass: 359.257 g/mol PubChem compound: 456199
The mechanism of action of pretomanid is thought to involve inhibition of the synthesis of cell wall lipids under aerobic conditions and generation of reactive nitrogen species under anaerobic conditions. Reductive activation of pretomanid by a mycobacterial deazaflavin (F420)-dependent nitro-reductase is required for activity under both aerobic and anaerobic conditions.
The activation of pretomanid, which takes place within the bacterial cell, is dependent on enzymes encoded by 5 genes: a co-factor F420-dependent nitroreductase named Ddn; a glucose-6-phosphate dehydrogenase named Fgd1; and the enzymes of the F420 biosynthetic pathway (FbiA, FbiB, and FbiC). Mutations in the 5 genes encoding these enzymes (ddn, fgd1, fbiA, fbiB, fbiC) have been associated with high level pretomanid resistance in vitro.
Not all isolates with increased minimum inhibitory concentrations (MICs) have mutations in these genes, suggesting the existence of at least one other mechanism of resistance.
Pretomanid does not show cross-resistance with any currently used anti-tuberculosis drugs, except for delamanid where cross-resistance has been demonstrated in vitro. This is likely to be due to pretomanid and delamanid being activated via the same pathway, see above. Only one case of acquisition of pretomanid resistance has been observed thus far in trials sponsored by TB Alliance.
The pharmacokinetic properties of pretomanid are similar in adult healthy patients and in adult tuberculosis-infected patients.
The absolute bioavailability of pretomanid has not been established. Two mass balance studies have indicated that the absolute bioavailability is greater than 53% and 64%.
The median tmax values range from 4 to 5 hours. Administration of 200 mg pretomanid with a high-fat, high-calorie meal increased mean Cmax by 76% and mean AUC0-inf by 88% as compared with administration in the fasted state.
The binding of pretomanid to human plasma proteins is 86.4%, so the fraction unbound (fu) is 13.6%. Human serum albumin binding was similar (82.7%), indicating that binding to albumin is responsible for the human plasma protein binding of pretomanid. The mean apparent volume of distribution (Vd/F) after a single dose of 200 mg in the fed state was 97 L when the mean weight was 72 kg.
The metabolic profile of pretomanid has not been completely elucidated. Pretomanid is extensively metabolised with over 19 metabolites identified through multiple metabolic pathways. In the mass-balance study, pretomanid had a half-life of 16 hours, while that of total radioactivity was 18 days, indicating the presence of partially unidentified long-lived metabolites.
In vitro, pretomanid was moderately metabolized by CYP3A4. A role of CYP3A4 was further supported by a clinical drug interaction study with CYP3A4 inducers. Nitro-reduction within Mycobacterium tuberculosis and potentially in gastrointestinal microflora is also involved in the metabolism of pretomanid.
Pretomanid is not a substrate of cytochrome P450 (CYP) 2C9, 2C19 or 2D6 in vitro.
The recovery of total radioactivity following a single dose of 14C-preotmanid was approximately 90% with about 53-65% excreted in the urine and 26-38% in faeces.
Pretomanid, at clinically relevant concentrations, is not a substrate or inhibitor for the transporters, bile salt export pump (BSEP), multidrug and toxin extrusion protein (MATE)1, MATE2-K, organic anion transporter (OAT)1, OAT1B1 and organic cation transporter (OCT)1. Pretomanid is not a substrate of OAT3, breast cancer resistance protein (BCRP), P-glycoprotein (P gp), OCT2 and organic anion-transporting polypeptide (OATP)1B3. The potential of pretomanid to inhibit P gp, OATP1B3, OCT2 and BCRP has not been investigated at clinically relevant concentrations.
Apparent clearance (CL/F) after a single dose was 7.6 and 3.9 l/h in the fasted and fed states, respectively. The elimination half-life was 17 hours.
In the fasted state, bioavailability decreased with increasing doses (50 to 1500 mg/day), with absorption saturation above 1000 mg. In the fed state, there were no significant changes in bioavailability across doses of 50 mg through 200 mg.
The pharmacokinetics of pretomanid has not been established in patients with impaired hepatic function.
The pharmacokinetics of pretomanid has not been established in patients with impaired renal function.
The pharmacokinetics of pretomanid have not been established in the paediatric population.
There is limited clinical data (n=5) on the use of pretomanid in elderly patients (≥65 years).
There were no clinically meaningful differences in the pharmacokinetics of pretomanid between Black and Caucasian patients. The pharmacokinetics of pretomanid have not been established in other racial populations.
Cataracts developed in rats given pretomanid at 300 mg/kg/day for 13 weeks with 7-fold the maximum recommended human dose (MRHD) exposure and at 100 mg/kg/day for 26 weeks with 3-4-fold MRHD exposure. The cataracts were not present at the end of dosing in monkeys given oral pretomanid at 450 mg/kg/day (10.5-fold of MRHD exposure) for 4 weeks and 300 mg/kg/day (5.4-fold MRHD exposure) for 12 more weeks, but observed in 2 of 12 monkeys during the 13-week post treatment recovery period. In a subsequent study in monkeys, cataracts were not observed following 13 weeks treatment with up to 300 mg/kg/day oral pretomanid (5-fold of MRHD exposure) or during the 20 week post treatment recovery period. Additionally, no cataracts were observed in repeat-dose toxicity studies of up to 9 months in monkeys (approximately 2-3-fold of MRHD exposure). In addition, in a 2-year carcinogenicity study in rats, pretomanid resulted in an increased incidence of cataracts at 10 mg/kg/day, resulting in an exposure in the same range as at the MRHD. The clinical relevance of this finding is unknown.
In repeat dose studies in rats, convulsions were observed at systemic exposures 4- to 10-fold higher than the clinical exposure at the MHRD of 200 mg/day (Cmax = 3.1 μg/ml and AUC0-24 = 57 h×μg/ml). In repeat dose studies in monkeys, convulsions were seen at exposures 2- to 8-fold higher than exposure at the MHRD. In both species, convulsions were observed at lower exposures during the longer duration studies (6-month rat and 9-month monkey). The mechanism of convulsions in nonclinical studies with pretomanid is unknown. The clinical relevance of this finding is unknown.
Pretomanid has the potential to affect cardiac repolarisation via blockade of hERG potassium channels and/or other cardiac ion channels including Nav1.5 and KCNQ1/minK.
Testicular toxicity was observed in rats and mice without exposure margin to the MRHD. Decreased fertility to complete infertility was observed in male rats treated with oral pretomanid. There were no direct effects of pretomanid on reproductive organs in monkeys given oral pretomanid for 3-months and 9-months. Decreased sperm motility, total sperm count and increased abnormal sperm ratio were observed in monkeys. Based upon the preclinical data, rodents are susceptible to pretomanid-induced testicular injury. Serum levels of the male reproductive hormones are biomarkers that are altered in association with this injury. In the preclinical study of primates, no pretomanid-related alterations in testis or male reproductive hormones were observed.
Non-clinical data reveal no special hazard for humans based on conventional studies of embryo-foetal development and peri-postnatal development.
Transfer of pretomanid from dam to pup via breast milk was studied in rats. After 14 days dosing of 20 mg/kg/day, the mean maternal plasma concentration 6 hours post dose was 2.84 μg/ml, which is similar to the mean steady state Cmax for 200 mg pretomanid in humans. At the same time, the mean concentration in milk was 4.07 μg/ml, and the mean plasma concentration in rat pups was 0.119 μg/ml. The concentration of pretomanid in rat milk does not necessarily predict the concentration of pretomanid in human milk.
No mutagenic or clastogenic effects were detected in conventional genotoxicity studies with pretomanid. A circulating metabolite of pretomanid, M50, was mutagenic in a bacterial reverse mutation assay. No carcinogenic potential was revealed in a 6-month study in transgenic mice where this metabolite is produced. In a 2-year study in rats, an increased incidence of Leydig cell adenomas was observed at a dose of 10 mg/kg/day. The observation is likely of limited relevance to humans.
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