NUZOLVENCE Oral suspension Ref.[116102] Active ingredients: Zoliflodacin

The ratio of the unbound plasma zoliflodacin area under the concentration-time curve from time of dosing extrapolated to infinity to the zoliflodacin MIC (fAUC_0-inf/MIC) is the best predictor of efficacy based on in vitro models of infection.

Cardiac Electrophysiology

A thorough QTc study of single oral doses of zoliflodacin 2 g and 4 g (not approved doses of NUZOLVENCE) was conducted in 72 healthy subjects aged 18 to 45 years. A concentration-dependent increase in QTc interval was observed in the thorough QTc study. Based on the observed relationship, clinically significant QTc interval prolongation is not expected at the maximum recommended single dose of NUZOLVENCE.

Zoliflodacin, as single doses, generally displayed dose-proportional increases in exposure up to 800 mg (0.27 times the recommended dosage). Increases above 800 mg led to slightly less than dose-proportional increases in exposure up to 4 g (1.3 times the recommended dosage).

The pharmacokinetic properties of zoliflodacin in healthy subjects are displayed in Table 4.

Table 4. Pharmacokinetic Properties of Zoliflodacin in Healthy Subjects:

Abbreviations: AUC = area under the concentration-time curve; CL/F=apparent total body clearance; C_max = maximum drug concentration; CYP = Cytochrome P450; %GCV = % geometric coefficient of variation; T_½ = elimination half-life; T_max = the time to C_max; Vz/F=apparent volume of distribution.
^a Based on studies with a moderate-fat, moderate-calorie meal consisting of approximately 462 kcal (39% fat, 51% carbohydrates, and 10% protein) or a high-fat, high-calorie meal consisting of approximately 884 kcal (estimated to contain approximately 55% fat, 29% carbohydrates, 16% protein).
^b Non-CYP-mediated clearance has not been fully characterized.

The predicted zoliflodacin exposure parameters in adult patients with uncomplicated urogenital gonorrhea are presented in Table 5.

Table 5. Zoliflodacin Exposures in Patients with Uncomplicated Urogenital Gonorrhea:

Abbreviations: AUC_0-inf = area under the concentration-time curve from time zero to infinity; C_max = maximum drug concentration.
^* Data presented as geometric mean (%CV) based on post hoc parameters from 24 patients enrolled in the Trial 1 (weight range 48.2 to 112.3 kg) who received zoliflodacin 3 g after a low/moderate fat meal.

Effect of Food

Following administration of the 3 g dose of NUZOLVENCE with a moderate-to-high-fat meal, zoliflodacin C_max was increased by approximately 1.5-fold and the AUC_0-inf was increased by approximately 1.5- to 2-fold. With a high-fat, high-calorie meal (consisting of approximately 884 kcal, 55% fat, 29% carbohydrates, 16% protein), the fed vs. fasted ratios of adjusted geometric means (90% CI) AUC_0-inf and C_max were 2.01 (1.85, 2.18) and 1.52 (1.39-1.67), respectively. With a moderate-fat, moderate-calorie meal (consisting of approximately 462 kcal, [39% fat, 51% carbohydrates, and 10% protein), the fed vs. fasted ratios of adjusted geometric means (90% CI) AUC_0-inf and C_max were 1.53 (1.45, 1.61) and 1.49 (1.38, 1.61), respectively.

Specific Populations

No clinically significant differences in the pharmacokinetics of zoliflodacin were observed based on age (18 to 55 years old), sex, and race (White 61%, Black 28%, Asian 8%).

Body Weight

There is an inverse relationship between body weight and zoliflodacin exposure. Simulations were conducted under moderate-fat/moderate-calorie conditions similar to Trial 1 (e.g., meals with 400-500 calories, <50% fat) to inform dosing conditions. Considering both the weight and food effects, patients weighing 35 kg to less than 50 kg should take NUZOLVENCE on an empty stomach and patients weighing 50 kg or more should take NUZOLVENCE with food [see Dosage and Administration (2.3)]. There are no clinical data in patients weighing less than 35 kg.

Pediatric Patients

There are no pharmacokinetic data in pediatric patients. Using modeling and simulation, the recommended dosage with administration based on weight is expected to result in comparable plasma exposures of zoliflodacin in pediatric patients 12 years of age and older and weighing at least 35 kg as observed in healthy adults [see Use in Specific Populations (8.4)].

Drug Interaction Studies

Clinical Studies and Model Informed Approaches

In a clinical drug-drug interaction study in 18 healthy subjects, the strong CYP3A4 inhibitor (and P-gp inhibitor) itraconazole, administered as a 400 mg loading dose followed by 200 mg once daily for 6 days, increased zoliflodacin systemic exposure (AUC_0-inf) by approximately 1.4-fold with minimal changes in peak concentrations (C_max) of zoliflodacin, when zoliflodacin was administered under fasted conditions. Co-administration with a strong CYP3A4 inhibitor is unlikely to translate to a clinically significant safety risk relative to NUZOLVENCE administered alone.

Co-administration of zoliflodacin with CYP3A4 inducers, rifampin and efavirenz, is predicted to reduce the geometric mean zoliflodacin exposure (AUC_0-inf) by approximately 56 and 41%, respectively [see Contraindications (4) and Drug Interactions (7.1)].

In Vitro Studies

Clearance of zoliflodacin via metabolism by CYP- and non-CYP-mediated pathways is the major clearance mechanism for zoliflodacin.

CYP phenotyping studies indicated that CYP-mediated metabolism of zoliflodacin is via CYP3A4 (68%), with lesser contributions from CYP1A2 (14%), CYP2C9 (10%), CYP2C8 (5%), and CYP2C19 (2.7%). Enzymes for the non-CYP metabolism have not been identified.

Zoliflodacin inhibited CYP2C8, CYP2C9, and CYP2C19 at IC₅₀ values that were approximately 14-to 28-fold higher than the anticipated unbound therapeutic plasma concentrations (total concentrations 2.5 to 5-fold higher). Zoliflodacin was not an inducer of CYP1A2, CYP2B6, and CYP3A4 in inducible human hepatocyte-like HepaRG cells at clinically relevant concentrations.

Zoliflodacin is a substrate for P-gp and BCRP and possible substrate for OATP1B1/3.

Zoliflodacin is not an inhibitor for OCT2, MATE1, MATE2K at clinically relevant concentrations. Zoliflodacin is an inhibitor of P-gp, BCRP, OAT1, OAT3, OATP1B1, and OATP1B3.

Mechanism of Action

Zoliflodacin is a spiropyrimidinetrione inhibitor of the bacterial type II topoisomerases (DNA gyrase and topoisomerase IV), which are required for DNA synthesis. Zoliflodacin binds within the cleaved DNA–gyrase complex, blocking re-ligation, and interacts with conserved amino acids in the gyrase B subunit.

Resistance

Resistance to spiropyrimidinetriones is associated with mutations in the bacterial type II topoisomerases (DNA gyrase and DNA topoisomerase IV) and efflux pumps. Zoliflodacin primarily targets DNA gyrase B in N. gonorrhoeae. Additionally, zoliflodacin shows reduced in vitro activity due to the up-regulation of efflux pumps such as MtrCDE, MacAB, and NorM. Resistance to zoliflodacin due to spontaneous mutations occurs at mutation frequencies of <5.2 x 10^-9 to <1.7 x 10^-8 at 8 times the MIC.

Cross-resistance has not been identified with other classes of antimicrobials, including penicillins, cephalosporins, aminoglycosides, macrolides, fluoroquinolones and tetracyclines.

Interaction with Other Antimicrobials

In vitro studies showed no antagonism between zoliflodacin and other antimicrobial drugs including ceftriaxone, cefixime, ciprofloxacin, spectinomycin, gentamicin, and tetracycline.

Antimicrobial Activity

Zoliflodacin has been shown to be active against the following microorganisms both in vitro and in clinical infections [see Indications and Usage (1)]:

Gram-negative bacteria

Neisseria gonorrhoeae

Susceptibility Test Methods

For specific information regarding susceptibility test interpretive criteria, and associated test methods and quality control standards recognized by FDA for this drug, please see https://www.fda.gov/STIC.

Carcinogenesis

Carcinogenicity studies have not been conducted with zoliflodacin.

Mutagenesis

Zoliflodacin was not genotoxic in the mouse lymphoma assay (MLA) and rat in vivo micronucleus assay. In the Ames bacterial reverse mutation assay, zoliflodacin was mutagenic in the TA102 strain, consistent with its pharmacologic action as a bacterial topoisomerase II inhibitor.

Impairment of Fertility

Male Fertility

In male rats, once daily oral administration of zoliflodacin for 4 weeks resulted in dose-related effects on fertility. At 1000 mg/kg/day (exposures 8-fold the MRHD based on AUC), males were completely infertile. At 500 mg/kg/day (exposures 4-fold the MRHD) fertility was reduced by 31%, with decreased pregnancy rates and increased pre- and post-implantation loss. After a 29-day recovery period, full recovery of fertility was observed; however, minimal to mild testicular tubular degeneration persisted after a 57-days recovery period. No zoliflodacin-related effects on fertility or testicular histopathology were observed at 200 mg/kg/day (exposures 2.4-fold the MRHD).

In a non-GLP study in rats, minimal exfoliation of germinal epithelial cells/immature sperm was observed in the testes at 1000 mg/kg/day and in the epididymides at 500 and 1000 mg/kg/day following 14 days of dosing (exposures greater than or equal to 2.8-fold the MRHD). Similar minimal epididymal findings occurred after 2-days of dosing at 1000 and 2000 mg/kg/day (exposures at and above 4-fold the MRHD).

After 4 weeks of daily zoliflodacin administration in rats, minimal to mild testicular degeneration and cellular debris in the epididymides were observed at or above 500 mg/kg/day (exposures 7.2-fold the MRHD). The microscopic findings, at a dose equivalent to exposures 10.7-fold the MRHD, were partially reversed after a 3-month recovery period. No adverse effects were reported at 200 mg/kg/day (exposures 3.3-fold the MRHD).

In dogs, 4 weeks of daily zoliflodacin administration produced mild to moderate testicular degeneration and moderate epididymides cellular debris at and above 200 mg/kg/day (exposures 7.5-fold the MRHD). No adverse effects were reported at 100 mg/kg/day (exposures 2.3-fold the MRHD). Findings were not present after a 3-month recovery period, although minimal to mild decreased spermatogenesis persisted in 2 of 3 dogs administered 500 mg/kg/day (exposures 8.1-fold the MRHD).

Female Fertility

In female rats, oral administration of zoliflodacin at 1000 mg/kg/day (exposures 12.7-fold the MRHD, extrapolated from nonpregnant rats) for 2 weeks prior to mating reduced pregnancy rates. No effects on pregnancy rates or embryo-fetal survival were observed at 500 mg/kg/day (7.9-fold the MRHD).

A total of 930 patients with suspected uncomplicated gonorrhea due to Neisseria gonorrhoeae were randomized in an open-label, active-controlled, multicenter, multinational trial (NCT03959527; Trial 1). Patients were randomized 2:1 to receive a single, oral, 3 g dose of NUZOLVENCE or a combination of a single intramuscular 500 mg dose of ceftriaxone and a single 1 g oral dose of azithromycin. Patients were eligible for enrollment if they were ≥12 years old and ≥35 kg. Patients with confirmed or suspected complicated or disseminated gonorrhea were excluded from the study.

The primary analysis population was the microbiologic intent-to-treat (micro-ITT) urogenital population, which included patients who had N. gonorrhoeae isolated at baseline from the urethra or cervix and who were not infected with a strain that showed resistance to both ceftriaxone and azithromycin at baseline. The micro-ITT urogenital population consisted of 744 patients (506 for NUZOLVENCE and 238 for ceftriaxone and azithromycin).

The demographic and baseline characteristics in the micro-ITT urogenital population were comparable between treatment groups. In total, 91% were male; 55% Black, 31% Asian, 13% White, and 4% Hispanic or Latino; the mean age was 30 years (range: 16 to 73) and the mean weight was 70 kg (range: 37 to 139 kg). The primary efficacy endpoint was microbiological cure as determined by confirmed bacterial eradication of N. gonorrhoeae at the urogenital body site at the test of cure (TOC) visit (Day 4 to 8) and was assessed in the micro-ITT urogenital population.

Table 6 shows the primary endpoint of microbiological cure rates at the urogenital site at TOC in the micro-ITT urogenital population. Trial 1 demonstrated non-inferiority of NUZOLVENCE to the combination of ceftriaxone and azithromycin.

Table 6. Microbiological Cure Rates at the Urogenital Site at TOC, Micro-ITT Urogenital Population:

TOC = Test of Cure; micro-ITT = microbiological Intent to Treat; CI=confidence interval; n = number of patients in a subcategory; N = number of patients in the specified population.
^a Calculated with the Newcombe score method for the NUZOLVENCE – (ceftriaxone and azithromycin) treatment difference
^b Microbiological cure is defined as negative or indeterminate Neisseria gonorrhoeae (NG) culture at the urogenital site at the TOC visit. There were no indeterminate NG cultures at the urogenital site at TOC.
^c Nonassessable outcomes were due to missed TOC visits, unobtainable specimens, or TOC visits out of window.