Gepotidacin

BRAND NAMES

Gepotidacin, marketed under the brand name, is an antibiotic used to treat urinary tract infections. It belongs to the triazaacenaphthylene class and acts as an inhibitor of bacterial Type II topoisomerases.

MECHANISM OF ACTION

Gepotidacin exerts its antibacterial effect by inhibiting two essential bacterial enzymes DNA gyrase and topoisomerase IV which play a critical role in DNA replication. As a first-in-class triazaacenaphthylene antibiotic, it binds to unique sites on these enzymes, forming stable DNA cleavage complexes that disrupt their function, ultimately leading to bacterial cell death. This dual-target mechanism is novel and significantly reduces the likelihood of resistance, as it would require simultaneous mutations in both enzymes for bacteria to evade its action.

PHARMACOKINETICS

Absorption

Gepotidacin is well-absorbed orally, with studies showing it reaches peak plasma concentration in approximately 1 to 4 hours. Its overall absorption is not significantly affected by food, although a meal may cause a slight delay in reaching peak concentration. The medication has an oral bioavailability of about 45%, with systemic exposure increasing in a dose-proportional manner. Gepotidacin is primarily metabolized by the enzyme CYP3A4, and its absorption and overall exposure are significantly increased in patients with severe renal or hepatic impairment.

Distribution

Gepotidacin exhibits a mean steady-state volume of distribution (Vss) of 172.9 litres, indicating extensive distribution into body tissues. It is 25% to 41% bound to plasma proteins, suggesting a moderate degree of protein binding. The drug has a terminal elimination half-life of approximately 9.3 hours, with a total clearance rate of 33.4 litres per hour, reflecting its elimination from the body through both renal and non-renal pathways.

Metabolism

Gepotidacin is primarily metabolized through oxidative pathways involving the cytochrome P450 (CYP) enzyme CYP3A4, though much of it is excreted unchanged. Approximately 13–19% of the dose is eliminated via metabolism, with a key circulating metabolite known as M4. Most of the drug is excreted in the feces (~52%) and urine (~31%), with the urinary route being the major pathway for the absorbed portion.

Excretion

Gepotidacin is eliminated from the body through a combination of fecal and urinary excretion. After an oral dose, approximately 52% is eliminated in the feces and about 31% is eliminated in the urine. 

PHARMACODYNAMICS

Gepotidacin is a first-in-class, novel bacterial topoisomerase inhibitor (NBTI) that selectively and bactericidally inhibits bacterial DNA gyrase and topoisomerase IV. This dual-targeting mechanism is distinct from that of fluoroquinolones, which provides activity against bacteria, including those with fluoroquinolone resistance. 

DOSAGE AND STRENGTHS

Gepotidacin is available as oral tablets, each containing 750 mg of the active drug. It is administered as 1,500 mg (two 750 mg tablets) taken twice, 12 hours apart, within a single day. Gepotidacin can be taken with or without food, and the tablets should be swallowed whole with water not crushed or chewed.

DRUG INTERACTIONS

Gepotidacin interacts with several medications primarily through its metabolism via the CYP3A4 enzyme, its potential to prolong the heart's QTc interval, and its reversible anticholinesterase activity. Strong CYP3A4 inhibitors (like itraconazole) and inducers (like rifampin) can increase or decrease gepotidacin's concentration, respectively, and must be avoided. The risk of life-threatening heart rhythm issues is heightened when gepotidacin is combined with other QTc-prolonging drugs, and this combination should be avoided. Additionally, as an acetylcholinesterase inhibitor, gepotidacin can increase the effects of other anticholinesterase medications (like donepezil) or counter the effects of systemic anticholinergic drugs. Close monitoring is required for specific drugs like digoxin, which can have its levels increased by gepotidacin.

FOOD INTERACTIONS

Based on FDA information, there are no known food or drink interactions with gepotidacin. However, the medication should be taken with food to reduce common gastrointestinal side effects like diarrhea and nausea. Taking doses approximately 12 hours apart after a meal can improve tolerability. It is unknown if alcohol affects the medication, but it's best to limit intake, as gepotidacin can cause dizziness.

CONTRAINDICATIONS

Gepotidacin is contraindicated in patients with a severe hypersensitivity to the drug. It should be avoided in patients with a history of QTc interval prolongation or other pre-existing cardiac disease. The medication is also not for use with strong CYP3A4 inhibitors or in patients with severe kidney or liver impairment, as these conditions increase drug exposure and raise the risk of QTc prolongation. Caution is also needed with other cholinergic or anticholinergic drugs. 

SIDE EFFECTS

Common side effects:

• Diarrhea.

• Nausea.

• Abdominal pain.

• Vaginal yeast infection.

• Headache.

• Dizziness.

• Gas (flatulence).

Serious side effects:

• QTc prolongation.

• Clostridioides difficile infection.

• Increased cholinergic effects.

• Allergic reactions.

OVERDOSE

• Heart rhythm problems (QTc prolongation):

• Fast, pounding, or irregular heartbeat.

• Dizziness, feeling lightheaded, or fainting.

• Chest pain or tightness.

• Trouble speaking clearly or slurred speech.

• Muscle spasms.

• Increased sweating (hyperhidrosis).

• Excessive salivation (hypersalivation).

• Seizures.

• Worsening heart rhythm issues, such as a very slow heartbeat (bradycardia).

• Bronchospasm (tightening of the airways).

TOXICITY

Gepotidacin is an antibiotic with generally mild, dose-dependent gastrointestinal side effects like diarrhea and nausea. However, it carries more serious risks, including dose-related QTc prolongation that can cause heart rhythm abnormalities, acetylcholinesterase inhibition with potentially severe cholinergic effects, and life-threatening hypersensitivity reactions. It is also contraindicated in patients with severe kidney or liver impairment and those with a history of heart rhythm issues.