Addition of Probenecid to Penicillin-V Therapy

Participants will be screened and consented to attend Imperial College Clinical Research Facility (CRF) at Hammersmith Hospital on two study visits, at least 7 days apart. For one visit (randomised), participants will be required to take penicillin-V only. For their other visit, they will take penicillin-V plus probenecid at standard recommended dose. Prior to the study visits, participants may be required to have taken 36-hours of penicillin +/- probenecid, documenting this in a dosing diary. On arrival at the CRF, the participant will take an observed dose of penicillin +/- probenecid. They will undergo blood draw via needle phlebotomy or a cannula (participant choice) at 45 and 180 minutes post the observed. Samples will be spun down and frozen at -80oC. They will subsequently be analysed using an in-house HPLC-MS/MS methodology to determine total and free-unbound drug concentration.

For analysis, data from this study will be pooled with rich PK data from a prior study that assessed plasma concertation of penicillin-V in healthy volunteers. Pmetrics in R will be used to model the data looking to explore the effect of probenecid on clearance of free-penicillin-V. Probability of target attainment for streptococci species will also be estimated to evaluate the potential clinical impact of the addition of probenecid to routine penicillin-V use. Rich PK data for intravenous benzylpenicillin will be used to estimate PK-PD target attainment and PTAs for intravenous formulations, allowing direct comparison of oral and IV regimes.

Inclusion criteria

• Adult healthy volunteers (>18 years old).
• Previously taken penicillin-based antibiotics without allergic response.
• Estimated Glomerular Filtration Rate (eGFR) > 90.

Exclusion criteria

• Lacking capacity to consent.
• Documented allergy to penicillin, other beta-lactam antibiotics, or probenecid.
• History of G6PD Deficiency.
• Known blood dyscrasias.
• Anaemia (Hb < 12g/dL female, 13g/dL males).
• Abnormal liver function (ALT, AST, ALP or bilirubin > ULN).
• eGFR < 90.
• Pregnant or likely to become pregnant during study period.
• Breastfeeding women.
• Symptoms consistent with active infection.
• History of gout or uric acid kidney stones.
• Taking regular medication that may interact with probenecid including, but not limited to methotrexate, lorazepam, acetaminophen, oral hypoglycaemic medication, sulfa containing drugs, non-steroidal anti-inflammatory drugs.
• History of evidence of any medical, neurological, or psychological condition that would expose the subject to an undue risk of a significant adverse event or interfere with study assessments during the course of the trial as determined by the clinical judgement of the investigator.
• Recent involvement in other research (within prior 3 months).