Probenecid

Probenecid is a chemically synthesised substance classified as a uricosuric and renal tubular transport blocking agent (ATC code M04AB01). It is authorised as a medicine under the trade name SANTURIL 500 mg comprimé sécable, supplied by Lipomed GmbH, and is also known as benecid, probecid, or probenecid acid.^[4][5] In the registered trials, probenecid appears as the test substance in one trial, while two other trials investigate PTI5803, a probenecid formulation.^[1][3][2]

Table of contents

• What is probenecid?
• How does probenecid work?
• Which conditions is it used or studied for?
• How is probenecid given?
• What do the clinical trials show?
• What side effects are known?

What is probenecid?

Probenecid is a uricosuric and renal tubular transport blocking agent, a chemical substance first developed as a way to increase the excretion of uric acid from the body.^[4] It is the prototypical uricosuric agent, meaning it serves as the reference compound for this class of medicines.^[5] Probenecid is authorised as a medicine in France under the name SANTURIL 500 mg comprimé sécable, with the authorisation held by Lipomed GmbH.^[1] The product information from the US label describes probenecid tablets of 500 mg for oral administration.^[4]

How does probenecid work?

Probenecid inhibits the tubular reabsorption of urate in the kidneys, which increases the urinary excretion of uric acid and decreases serum urate levels. Effective uricosuria reduces the miscible urate pool, retards urate deposition, and promotes resorption of urate deposits.^[4] Probenecid also inhibits the tubular secretion of penicillin and usually increases penicillin plasma levels, with a 2-fold to 4-fold elevation demonstrated for various penicillins. It has been reported to inhibit the renal transport of many other compounds, including aminohippuric acid, aminosalicylic acid, indomethacin, and sulfonamides.^[4] In the nervous system, the registered trials are exploring whether probenecid and its formulation PTI5803 can influence seizure activity, although the exact mechanism in epilepsy is not described in the trial records.^[1][3]

Which conditions is it used or studied for?

• Gout and gouty arthritis — probenecid is authorised for the treatment of hyperuricemia associated with gout and gouty arthritis, where high uric acid levels cause joint pain and inflammation.^[4]
• Focal epilepsy — a Phase 2 trial is studying probenecid for cluster seizures during pre-surgical video-EEG monitoring in patients with focal epilepsy.^[1]
• Drug-resistant seizures associated with focal cortical dysplasia — two Phase 2 trials are studying PTI5803, a probenecid formulation, as adjunctive therapy in patients aged 14 years and older with drug-resistant seizures related to focal cortical dysplasia.^[3][2]

How is probenecid given?

Probenecid is given orally as a tablet. The authorised product in France is SANTURIL 500 mg comprimé sécable, a 500 mg tablet that can be divided.^[1] The US product information describes probenecid tablets of 500 mg for oral administration.^[4] In the focal epilepsy trial, probenecid is administered orally at a total dose of 3 grams.^[1] The PTI5803 formulation is given as an oral solution of 16 ml.^[3][2]

What do the clinical trials show?

Three interventional Phase 2 trials are registered, all currently authorised. One trial investigates probenecid itself in 192 participants with focal epilepsy, while two trials investigate the probenecid formulation PTI5803 in 15 participants each with drug-resistant seizures associated with focal cortical dysplasia.^[1][3][2]

The focal epilepsy trial measures the proportion of patients without seizure between 60 minutes and 12 hours after probenecid or placebo administration, assessed by a neurologist on video and EEG recording, in patients experiencing cluster seizures defined as at least two epileptic seizures lasting less than 10 minutes occurring within 6 hours or less during pre-surgical hospital video-EEG monitoring.^[1]

The two PTI5803 trials assess safety and tolerability as their primary outcomes. The first measures the severity and frequency of treatment-emergent adverse events and serious adverse events, clinically significant changes in vital signs, laboratory findings, physical examination, or 12-lead ECG, increase in suicide risk as assessed by the C-SSRS, and potential effects on concomitant antiseizure medication levels.^[3] The extension study measures adverse events, clinically significant findings in physical examinations, vital signs, body weight and height, laboratory tests, or 12-lead ECGs, and increase in suicide risk as assessed by the C-SSRS.^[2]

What side effects are known?

The supplementary sources provided do not describe specific side effects of probenecid in detail. The US product label discusses drug interactions and the inhibition of renal transport of various compounds, but does not list adverse reactions in the provided excerpt.^[4] The trial records for PTI5803 list safety and tolerability as primary outcomes, indicating that side effects are being systematically assessed, but no specific side effects are reported in the registry data.^[3][2]