Addition of Probenecid to Penicillin-V Therapy

Infection, Bacterial Clinical Trial

— ADDPROPEN  

Official title:

Addition of Probenecid to Penicillin-V Therapy: an Open Label, Cross-over Study in Healthy Volunteers

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05082909
• Other study ID #: 21HH6936
• Status: Recruiting
• Phase: Phase 1/Phase 2
• Start date: December 21, 2021
• Est. completion date: October 2022

Study information

• Verified date: April 2022
• Source: Imperial College London
• Contact: Timothy Rawson, PhD
• Phone: 0208 383 3231
• Email: tmr07[@]ic.ac.uk
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This study aims to build on previous work characterising the PK of penicillin-V to explore the potential impact of probenecid on PK-PD target attainment. Achievement of the aims of this study would provide data to support the design of experimental studies exploring the clinical impact of probenecid on treatment outcomes and also provide a rationale for exploration of probenecid's effects on a larger number of beta-lactam antibiotics.

Hypothesis: Addition of probenecid to oral phenoxymethylpenicillin (penicillin-V) has a clinically relevant effect on pharmacokinetic-pharmacodynamic (PK-PD) target attainment.

Description:

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 50
• Est. completion date: October 2022
• Est. primary completion date: October 2022
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years and older

Eligibility

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).

Related Conditions & MeSH terms

• Bacterial Infections
• Infection, Bacterial

Intervention

Drug:
• Probenecid
Addition of 500mg QDS to oral penicillin.

Locations

Country	Name	City	State
United Kingdom	Imperial Clinical Research Facility	London

Sponsors (1)

Lead Sponsor	Collaborator
Imperial College London

Country where clinical trial is conducted

United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Measurement of total and unbound penicillin-V concentration	Measurement of blood concentration at 45 minutes post dose with and without probenecid.	45 minutes post an observed dose.
Primary	Measurement of total and unbound penicillin-V concentration	Measurement of blood concentration at 180 minutes post dose with and without probenecid.	180 minutes post an observed dose.
Secondary	Measurement of total and unbound probenecid concentration	Measurement of blood concentration at 45 minutes post observed penicillin-V dose with and without probenecid.	45 minutes post an observed dose.
Secondary	Measurement of total and unbound probenecid concentration	Measurement of blood concentration at 180 minutes post observed penicillin-V dose with and without probenecid.	180 minutes post an observed dose.