Addition of Probenecid to Penicillin-V Therapy (ADDPROPEN)

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

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.

Study Overview

• Status: Completed
• Conditions: Infection, Bacterial
• Intervention / Treatment: Drug: Probenecid

Detailed 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.

• Study Type: Interventional
• Enrollment (Actual): 21
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United Kingdom
  • London, United Kingdom
    • Imperial Clinical Research Facility

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Description

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).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Penicillin alone; Penicillin orally at dose of either 250mg, 500mg, 750mg QDS for 36 hours.	Drug: Probenecid; Addition of 500mg QDS to oral penicillin.
Experimental: Penicillin plus probenecid; Penicillin orally at dose of either 250mg, 500mg, 750mg QDS for 36 hours. PLUS Probenecid 500mg QDS for 36 hours.	Drug: Probenecid; Addition of 500mg QDS to oral penicillin.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
Measurement of Total and Unbound Probenecid Concentration	Measurement of blood concentration at 45 minutes post observed probenecid dose. Combined data for all participants given that the same dose of probenecid was taken by all participants.	45 minutes post an observed dose.
Measurement of Total and Unbound Probenecid Concentration	Measurement of blood concentration at 180 minutes post observed probenecid dose. Combined data for all participants given that the same dose of probenecid was taken by all participants.	180 minutes post an observed dose.

Collaborators and Investigators

• Sponsor: Imperial College London
• Investigators: Principal Investigator: Timothy Rawson, PhD, Imperial College London

Study record dates

Study Major Dates

• Study Start (Actual): December 21, 2021
• Primary Completion (Actual): July 7, 2022
• Study Completion (Actual): July 7, 2022

Study Registration Dates

• First Submitted: September 17, 2021
• First Submitted That Met QC Criteria: October 5, 2021
• First Posted (Actual): October 19, 2021

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: January 6, 2025
• Last Verified: January 1, 2025

More Information

Terms related to this study

• Keywords: Pharmacokinetics; Penicillin; Probenecid
• Additional Relevant MeSH Terms: Infections; Bacterial Infections and Mycoses; Bacterial Infections; Gout Suppressants; Antirheumatic Agents; Uricosuric Agents; Probenecid
• Other Study ID Numbers: 21HH6936

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Data will be shared upon reasonable request with appropriate permissions in place.
• IPD Sharing Time Frame: The protocol will be available from commencement of study. The clinical study report will be published within 12 months of completion of the study.
• IPD Sharing Access Criteria: Access via the study principle investigator or online publications.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No