PRETOMANID Tablet Ref.[10178] Active ingredients:

Cardiac Electrophysiology

A randomized, double-blind, placebo- and positive-controlled (moxifloxacin 400 mg), crossover, thorough QT study of pretomanid was performed in 74 healthy adult subjects. At 400 mg (2 times the approved recommended dosage) and 1,000 mg (5 times the approved recommended dosage) single doses of pretomanid, no significant QT prolongation effect was detected.

In Study 1, patients received the combination regimen of Pretomanid Tablets, bedaquiline, and linezolid for 6 months. No patient had QTcF intervals greater than 480 msec, and 1 subject had a post-baseline increase of QTcF of greater than 60 msec.

Pretomanid AUC and C_max were approximately dose proportional over a range of single oral doses from 50 mg (0.25 times the approved recommended dosage) to 200 mg (approved recommended dosage); at single doses greater than 200 mg and up to 1,000 mg (5 times the approved recommended dosage), AUC and C_max increased in a less than dose proportional manner. Steady-state pretomanid plasma concentrations were achieved approximately 4 to 6 days following multiple dose administration of 200 mg, and the accumulation ratio was approximately 2. Pharmacokinetic parameters following single and multiple 200 mg doses of pretomanid in healthy adult subjects are summarized in Table 3.

Table 3. Mean (SD) Pretomanid Pharmacokinetic Parameters in Healthy Adult Subjects Under Fasted and Fed Conditions:

ND – Not Determined.
* - AUC_96hr
^† - AUC_24hr
^‡ - Median (minimum, maximum)

Absorption

Effect of Food

Administration of an oral tablet dose of pretomanid with a high-fat, high-calorie meal (approximately 150, 250, and 500 to 600 calories from protein, carbohydrate, and fat, respectively) increased mean C_max by 76% and mean AUC_inf by 88% as compared with the fasted state (see also Table 3 above).

Distribution

The plasma protein binding of pretomanid is approximately 86.4%.

Elimination

See Table 3 above for estimates of apparent oral clearance and half-life of pretomanid.

Metabolism

Pretomanid is 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 of pretomanid.

Excretion

In healthy adult males receiving 1,100 mg oral ¹⁴C-radiolabeled pretomanid, a mean (SD) of 53% (3.4%) of a radioactive dose was excreted in urine and 38% (2.7%) in feces, primarily as metabolites; approximately 1% of the radioactive dose was excreted in the urine as unchanged pretomanid.

Specific Populations

No clinically significant differences in the pharmacokinetics of pretomanid were observed based on sex, body weight, race (Black, White, or other), pulmonary TB status (XDR, treatment intolerant or non-responsive MDR), or HIV status. The effect of renal or hepatic impairment on the pharmacokinetics of pretomanid is unknown.

Drug Interaction Studies

Clinical Studies

Efavirenz: Co-administration of 200 mg QD of pretomanid with efavirenz 600 mg QD for 7 days resulted in a decrease of pretomanid mean AUC by 35% and C_max by 28%. Mean AUC and C_max of efavirenz were not affected when given with pretomanid.

Lopinavir/ritonavir: Co-administration of 200 mg QD pretomanid with lopinavir/ritonavir 400/100 mg BID for 7 days resulted in a decrease of pretomanid mean AUC by 17% and C_max by 13%. Mean AUC and C_max of lopinavir were decreased by 14% and 17%, respectively, when given with pretomanid.

Rifampin: Co-administration of 200 mg QD pretomanid with rifampin 600 mg QD for 7 days resulted in a decrease of pretomanid mean AUC by 66% and C_max by 53%.

Midazolam: Co-administration of 400 mg (twice the approved recommended dosage) QD pretomanid for 14 days and a single 2 mg oral dose of midazolam on Day 14 resulted in a decrease in midazolam mean AUC by 15% and C_max by 16%, and an increase in 1-hydroxy midazolam mean AUC by 14% and C_max by 5%.

In Vitro Studies Where Drug Interaction Potential Was Not Further Evaluated Clinically

Cytochrome P450 (CYP) Enzymes: CYP3A4 plays a role in the metabolism of pretomanid, i.e., up to 20%. Pretomanid is not a substrate of CYP2C9, CYP2C19, and CYP2D6. Pretomanid is not an inhibitor of CYP1A2, CYP2C8, CYP2C9, CYP2C19, and CYP2D6 at clinically relevant concentrations based on in vitro studies. Pretomanid is not an inducer of CYP2C9, or CYP3A4.

Transporter Systems: In vitro studies indicate that pretomanid significantly inhibits the OAT3 drug transporter, which could result in increased concentrations of OAT3 substrate drugs at clinically relevant concentrations of pretomanid. No clinical drug-drug interaction studies have been conducted with OAT3 substrates.

In vitro studies indicated that pretomanid does not inhibit human OAT1, OCT1, OCT2, OAT1B1, OATP1B3, BCRP, BSEP, P-gp, MATE1, and/or MATE2-K mediated transport at clinically relevant concentrations of pretomanid. Pretomanid is not a substrate of OAT1, OAT3, OCT2, OAT1B1, OATP1B3, MATE1, MATE2-K, BCRP, and/or P-gp transporters.

Mechanism of Action

Pretomanid Tablet is a nitroimidazooxazine antimycobacterial drug. Pretomanid kills actively replicating M. tuberculosis by inhibiting mycolic acid biosynthesis, thereby blocking cell wall production. Under anaerobic conditions, against non-replicating 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 the deazaflavin-dependent nitroreductase, Ddn, which is dependent on the reduced form of the cofactor F₄₂₀. Reduction of F₄₂₀ is accomplished by the F₄₂₀-dependent glucose-6-phosphate dehydrogenase, Fgd1.

Resistance

Mutations in five M. tuberculosis genes (ddn, fgd1, fbiA, fbiB, and fbiC) have been associated with pretomanid resistance. The products of these genes are involved in bioreductive activation of pretomanid within the bacterial cell. 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. The in vitro frequency of resistance development to pretomanid ranged from 10^-7 to 10^-5 at 2 to 6 times the pretomanid MICs. Cross-resistance of pretomanid with other compounds in the same class has been observed.

Antimicrobial Activity

Pretomanid has demonstrated in vitro activity against the M. tuberculosis complex. Pretomanid has also demonstrated anti-M. tuberculosis activity in animal models of tuberculosis [see Indications and Usage (1)].

In murine tuberculosis models, the 3-drug combination of pretomanid, bedaquiline, and linezolid reduced bacterial counts in the lungs to a greater extent and resulted in fewer relapses at 2 and 3 months post-therapy compared to 2-drug combinations of pretomanid, bedaquiline, and linezolid.

In clinical Study 1, the pretomanid MIC was determined using the Mycobacterial Growth Indicator Tube (MGIT). The baseline pretomanid MIC for M. tuberculosis isolates in the study ranged from 0.06 to 1 mcg/mL.

Carcinogenesis

Carcinogenicity studies of pretomanid have not been completed.

Mutagenesis

No mutagenic or clastogenic effects were detected in both an in vitro bacterial reverse mutation assay and an in vitro mammalian chromosome aberrations assay using a Chinese hamster ovary cell line. Pretomanid was negative for clastogenicity in a mouse bone marrow micronucleus assay.

A metabolite of pretomanid was mutagenic in a bacterial reverse mutation assay. This metabolite represents approximately 6% of the human exposure (AUC) to pretomanid at the MRHD.

Fertility

In a fertility and general reproduction study in rats, male rats treated orally with pretomanid for 13 to 14 weeks had reduced fertility at 30 mg/kg/day and complete infertility at 100 mg/kg/day (approximately 1 and 2‑times the human exposure for a 200 mg dose, respectively). At 100 mg/kg/day, males had testicular atrophy including hypospermia in the epididymal tubules and focal epithelial hyperplasia of the epididymal tubular epithelium. Following a 10-week treatment-free period, these effects were partially reversed in male rats given pretomanid at 30 mg/kg/day but not at 100 mg/kg/day. These effects were associated with increased serum follicle-stimulating hormone and decreased serum inhibin B concentrations. There were no effects of pretomanid in male rats treated for 13 weeks at 10 mg/kg/day (approximately half of the human exposure for a 200 mg dose). Pretomanid did not affect mating behavior in female rats given oral pretomanid at 100 mg/kg/day for two weeks (approximately twice the human exposure).

Testicular toxicity was present in male mice treated orally for 13 weeks at 20 mg/kg/day [approximately equal to the human exposure (AUC) for a 200 mg dose]. There were no adverse testicular effects observed in mice given pretomanid at 6 mg/kg/day (0.2‑times the human exposure for a 200 mg dose).

Testicular toxicity was observed in male rats following 7 or 14 days of dosing with oral pretomanid at 100 mg/kg/day (approximately 2-times the human exposure for a 200 mg dose). The effects were partially reversible during a 6-month post treatment recovery period in rats treated with pretomanid for 7 days, but not 14 days.

In a 3-month study, decreased sperm motility and total sperm count, and increased abnormal sperm ratio were noted in sexually mature monkeys given ≥150 mg/kg/day (approximately 3 times the human exposure for a 200 mg dose).

Cataracts were observed in rats treated with pretomanid at doses of 300 mg/kg/day for 13 weeks or 100 mg/kg/day for 26 weeks. There were no cataracts observed in rats given oral pretomanid at 30 mg/kg/day (approximately 2 times the human exposure for a 200 mg dose) for 26 weeks.

In monkeys given oral pretomanid at 450 mg/kg/day for 4 weeks and 300 mg/kg/day for 12 more weeks, cataracts were not present at the end of dosing but developed during the 13‑week post treatment recovery period. In a subsequent study, cataracts were not observed following 13 weeks treatment with up to 300 mg/kg/day oral pretomanid or during the 20-week post treatment recovery period. Further, no cataracts were observed in monkeys given oral pretomanid at 100 mg/kg/day for 39 weeks with a 12-week post treatment recovery. This is approximately 1- to 2-times the human exposure for a 200 mg dose (AUC).

Study 1 (NCT02333799) was an open-label study conducted in three centers in South Africa in patients with XDR, treatment‑intolerant MDR, or non-responsive MDR pulmonary TB. Fifty-six (51%) patients were HIV-positive. The patients received a combination regimen of Pretomanid Tablets, bedaquiline, and linezolid for 6 months (extended to 9 months in 2 patients) with 24 months of follow-up; linezolid starting dose was either 600 mg twice daily or 1200 mg once daily. One hundred seven of the 109 patients enrolled were assessable for the primary efficacy analyses with two patients remaining in follow‑up for the primary outcome assessment.

Treatment failure was defined as the incidence of bacteriologic failure (reinfection – culture conversion to positive status with different M. tuberculosis strain), bacteriological relapse (culture conversion to positive status with same M. tuberculosis strain), or clinical failure through follow-up until 6 months after the end of treatment. Results are presented in Table 4. Of the 107 patients assessed, outcomes were classified as success for 95 (89%) patients and failure for 12 (11%) patients. The success rate significantly exceeded the historical success rates for XDR-TB based on a literature review. The outcomes were similar in both HIV negative and HIV positive patients.

Table 4. Outcomes Six Months After the End of Treatment:

TI/NR MDR-TB = treatment-intolerant or nonresponsive multidrug-resistant tuberculosis; XDR-TB = extensively drug resistant tuberculosis
* The patient died at Day 486.