Zoliflodacin

Zoliflodacin is an antibacterial drug. It 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.

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 zoliflodacin) 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 zoliflodacin.

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 1.

Table 1. 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 2.

Table 2. 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 zoliflodacin 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 zoliflodacin on an empty stomach and patients weighing 50 kg or more should take zoliflodacin with food. 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.

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 zoliflodacin 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.

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.