Gepotidacin

Gepotidacin is an antibacterial drug.

The 24-hour free‑drug AUC to minimum inhibitory concentration (MIC) ratio has been shown in animal infection and in vitro pharmacokinetic‑pharmacodynamic (PK‑PD) models to be the PK‑PD index predictive of gepotidacin antibacterial efficacy.

Cardiac Electrophysiology

The effect of gepotidacin on the QTc interval was evaluated in a randomized, active (moxifloxacin 400 mg) and placebo‑controlled, double‑blind cross‑over trial in healthy subjects who received single intravenous (IV) infusions of gepotidacin over 2 hours. A dose- and concentration‑dependent QTc prolongation effect of gepotidacin was observed. The mean placebo‑corrected change from baseline heart rate values around T_max were approximately 6 bpm at 1,000 mg IV (not an approved dosing regimen and route of administration) and approximately 10 bpm at 1,800 mg IV (not an approved dosing regimen and route of administration). The mean placebo‑corrected change from baseline QTcF values around T_max were 12 msec at 1,000 mg IV and 22 msec at 1,800 mg IV. The C_max of gepotidacin following a single 1,000 mg IV dose (not an approved dosing regimen and route of administration) is approximately 1.7 times that of the C_max at steady state for the 1,500 mg oral dose twice daily.

Pharmacokinetic Parameters

The pharmacokinetic properties of gepotidacin are summarized in the following table as mean (standard deviation [SD]) unless otherwise specified.

Pharmacokinetic Parameters of Gepotidacin:

^a Pharmacokinetic parameters are presented at steady state in patients with uUTI and eGFR greater than or equal to 90 mL/min after oral administration of gepotidacin 1500 mg every 12 hours over 5 days.
^b Studies evaluating the effect on food were performed with standard and moderate fat meal. Clinical studies were not performed with a high fat meal (1000 calories, 50% fat).

Specific Populations

Modelling and simulation analyses of gepotidacin showed no clinically relevant effect of age (12 to <18 years of age or 65 to 89 years of age), sex, race, or body weight (range: 40 kg to 140 kg) on gepotidacin exposure.

Patients with Renal Impairment

The pharmacokinetics of gepotidacin were evaluated in subjects with moderate renal impairment (eGFR 30 to 59 mL/min) and in subjects with severe renal impairment/end stage renal disease (ESRD) on intermittent hemodialysis and not on intermittent hemodialysis (eGFR <30 mL/min). Gepotidacin plasma C_max and AUC in subjects with moderate renal impairment were 1.2‑fold and 1.5‑fold higher than matched healthy controls, respectively. Gepotidacin plasma C_max and AUC in severe renal impairment/ESRD not on intermittent hemodialysis were 1.7-fold and 2.1‑fold higher than matched healthy controls, respectively. Gepotidacin plasma C_max and AUC in ESRD subjects requiring intermittent hemodialysis were 2.3‑fold and 2.5‑fold higher before intermittent hemodialysis than healthy matching subjects, respectively, and were 6.2‑fold and 4.2‑fold higher after intermittent hemodialysis than matched healthy controls, respectively.

Patients with Hepatic Impairment

Moderate hepatic impairment did not have a clinically relevant effect on gepotidacin pharmacokinetics. In subjects with severe hepatic impairment compared with subjects with normal hepatic function, gepotidacin plasma exposure parameters (C_max and AUC) were increased by approximately 1.9‑fold and 1.7‑fold, respectively.

Drug Interaction Studies

Clinical Drug Interaction Studies

Effect of CYP3A4 Inhibitors on the Pharmacokinetics of Gepotidacin: Concomitant administration of a strong inhibitor of CYP3A4 (itraconazole; 200 mg per day for 3 days), and a single 1,500 mg dose of gepotidacin resulted in an increase in the maximum concentration (C_max) of gepotidacin of approximately 1.4‑fold and area under the curve (AUC) of approximately 1.5‑fold.

Effect of CYP3A4 Inducers on the Pharmacokinetics of Gepotidacin: Concomitant administration of gepotidacin (single 1,500 mg dose) with a strong CYP3A4 inducer (rifampin; 600 mg once daily for 7 days) resulted in a decrease of 52% in gepotidacin plasma AUC_(0-∞).

Effect of Gepotidacin on Pharmacokinetics of Other Drugs: Concomitant administration of a single 0.5 mg dose of digoxin with two 3,000 mg doses of gepotidacin (an in vitro P‑glycoprotein inhibitor), given 12 hours apart (not an approved dosage of gepotidacin), resulted in a 1.5‑fold increase in the digoxin C_max (at 3 hours post dose), a 1.1‑fold increase in the digoxin AUC_(0-∞), and a delayed digoxin T_max.

Concomitant administration of midazolam (2 mg single dose) with gepotidacin (2 doses of 3,000 mg, given 12 hours apart; not an approved dosage of gepotidacin) resulted in a 1.9‑fold increase in midazolam AUC_(0-∞).

In-Vitro Drug Interaction Studies

In vitro, gepotidacin was not an inducer of CYP1A2, 2B6 or 3A4. In vitro, gepotidacin is not a substrate of any of the hepatic organic anion transporting polypeptides (OATPs) 1B1, 1B3, and 2B1, organic anion transporters (OATs) OAT1, OAT2 and OAT3, organic cation transporters (OCTs) OCT2 and OCT3.

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

In vitro, gepotidacin inhibited multidrug and toxin extrusion (MATEs) MATE1 (IC₅₀=16.6 µM), and MATE2‑K (IC₅₀=6.9 μM). In vitro, gepotidacin is a substrate of breast cancer resistance protein (max flux rate ratio of 11.0).