Infection, Bacterial
Conditions
Keywords
Penicillin, Probenecid, Pharmacokinetics
Brief 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.
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.
Interventions
DRUGProbenecid
Addition of 500mg QDS to oral penicillin.
Sponsors
Imperial College London
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Randomised, cross-over study
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
Yes
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).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Measurement of Total and Unbound Penicillin-V Concentration | 45 minutes post an observed dose. | Measurement of blood concentration at 45 minutes post dose with and without probenecid. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Measurement of Total and Unbound Probenecid Concentration | 45 minutes post an observed dose. | 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. |
Countries
United Kingdom
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Penicillin 250mg QDS THEN Penicillin 250mg QDS Plus Probenecid 500mg QDS Sequence:
1. Penicillin orally at dose of 250mg QDS for 36 hours.
2. Washout period
3. Penicillin orally at dose of 250mg QDS and probenecid 500mg QDS to oral penicillin for 36 hours. | 3 |
| Penicillin 500mg QDS THEN Penicillin 500mg QDS Plus Probenecid 500mg QDS Sequence:
1. Penicillin orally at dose of 500mg QDS for 36 hours.
2. Washout period
3. Penicillin orally at dose of 500mg QDS and probenecid 500mg QDS to oral penicillin for 36 hours. | 4 |
| Penicillin 750mg QDS THEN Penicillin 750mg QDS Plus Probenecid 500mg QDS Sequence:
1. Penicillin orally at dose of 750mg QDS for 36 hours.
2. Washout period
3. Penicillin orally at dose of 750mg QDS and probenecid 500mg QDS to oral penicillin for 36 hours | 4 |
| Penicillin 250mg QDS Plus Probenecid 500mg QDS THEN Penicillin 250mg QDS Sequence:
1. Penicillin orally at dose of 250mg QDS and probenecid 500mg QDS to oral penicillin for 36 hours
2. Washout period
3. Penicillin orally at dose of 250mg QDS for 36 hours. | 2 |
| Penicillin 500mg QDS Plus Probenecid 500mg QDS THEN Penicillin 500mg QDS Sequence:
1. Penicillin orally at dose of 500mg QDS and probenecid 500mg QDS to oral penicillin for 36 hours
2. Washout period
3. Penicillin orally at dose of 500mg QDS for 36 hours. | 6 |
| Penicillin 750mg QDS Plus Probenecid 500mg QDS THEN Penicillin 750mg QDS Sequence:
1. Penicillin orally at dose of 750mg QDS and probenecid 500mg QDS to oral penicillin for 36 hours
2. Washout period
3. Penicillin orally at dose of 750mg QDS for 36 hours. | 2 |
| Total | 21 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Overall Study | Protocol Violation | 0 | 0 | 1 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Penicillin 500mg QDS THEN Penicillin 500mg QDS Plus Probenecid 500mg QDS | Penicillin 250mg QDS THEN Penicillin 250mg QDS Plus Probenecid 500mg QDS | Total | Penicillin 750mg QDS Plus Probenecid 500mg QDS THEN Penicillin 750mg QDS | Penicillin 500mg QDS Plus Probenecid 500mg QDS THEN Penicillin 500mg QDS | Penicillin 250mg QDS Plus Probenecid 500mg QDS THEN Penicillin 250mg QDS | Penicillin 750mg QDS THEN Penicillin 750mg QDS Plus Probenecid 500mg QDS |
|---|---|---|---|---|---|---|---|
| Age, Continuous | 55 years STANDARD_DEVIATION 11 | 50 years STANDARD_DEVIATION 18 | 53 years STANDARD_DEVIATION 17 | 30 years STANDARD_DEVIATION 2 | 67 years STANDARD_DEVIATION 6 | 48 years STANDARD_DEVIATION 22 | 52 years STANDARD_DEVIATION 14 |
| Albumin | 41 g/L STANDARD_DEVIATION 2 | 42 g/L STANDARD_DEVIATION 3 | 41 g/L STANDARD_DEVIATION 2 | 43 g/L STANDARD_DEVIATION 1 | 40 g/L STANDARD_DEVIATION 2 | 41 g/L STANDARD_DEVIATION 3 | 41 g/L STANDARD_DEVIATION 2 |
| Creatinine | 68 micromol/L STANDARD_DEVIATION 6 | 62 micromol/L STANDARD_DEVIATION 5 | 68 micromol/L STANDARD_DEVIATION 9 | 78 micromol/L STANDARD_DEVIATION 5 | 70 micromol/L STANDARD_DEVIATION 7 | 64 micromol/L STANDARD_DEVIATION 3 | 69 micromol/L STANDARD_DEVIATION 2 |
| Height | 169 cm STANDARD_DEVIATION 10 | 167 cm STANDARD_DEVIATION 10 | 171.5 cm STANDARD_DEVIATION 7.8 | 179 cm STANDARD_DEVIATION 3 | 174 cm STANDARD_DEVIATION 4 | 171 cm STANDARD_DEVIATION 5 | 170 cm STANDARD_DEVIATION 5 |
| Race and Ethnicity Not Collected | — | — | 0 Participants | — | — | — | — |
| Region of Enrollment United Kingdom | 4 participants | 3 participants | 21 participants | 2 participants | 6 participants | 2 participants | 4 participants |
| Sex: Female, Male Female | 1 Participants | 1 Participants | 8 Participants | 0 Participants | 4 Participants | 1 Participants | 1 Participants |
| Sex: Female, Male Male | 3 Participants | 2 Participants | 13 Participants | 2 Participants | 2 Participants | 1 Participants | 3 Participants |
| Weight | 68 Kilograms STANDARD_DEVIATION 8 | 68 Kilograms STANDARD_DEVIATION 5 | 72 Kilograms STANDARD_DEVIATION 9 | 88 Kilograms STANDARD_DEVIATION 1 | 71 Kilograms STANDARD_DEVIATION 6 | 70 Kilograms STANDARD_DEVIATION 0 | 74 Kilograms STANDARD_DEVIATION 11 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 20 | 0 / 20 |
| other Total, other adverse events | 7 / 20 | 8 / 20 |
| serious Total, serious adverse events | 0 / 20 | 0 / 20 |
Outcome results
Primary
Measurement of Total and Unbound Penicillin-V Concentration
Measurement of blood concentration at 45 minutes post dose with and without probenecid.
Time frame: 45 minutes post an observed dose.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| 250mg Penicillin Arm 1 | Measurement of Total and Unbound Penicillin-V Concentration | Total penicillin concentration (mg/L) - penicillin alone | 2.07 mg/L | Standard Deviation 0.16 |
| 250mg Penicillin Arm 1 | Measurement of Total and Unbound Penicillin-V Concentration | Unbound penicillin concentration (mg/L) - penicillin alone | 0.39 mg/L | Standard Deviation 0.04 |
| 250mg Penicillin Arm 1 | Measurement of Total and Unbound Penicillin-V Concentration | Total penicillin concentration (mg/L) - penicillin plus probenecid | 4.83 mg/L | Standard Deviation 0.91 |
| 250mg Penicillin Arm 1 | Measurement of Total and Unbound Penicillin-V Concentration | Unbound penicillin concentration (mg/L) - penicillin plus probenecid | 1.58 mg/L | Standard Deviation 0.87 |
| 250mg Penicillin Arm 2 | Measurement of Total and Unbound Penicillin-V Concentration | Total penicillin concentration (mg/L) - penicillin plus probenecid | 7.45 mg/L | Standard Deviation 1.05 |
| 250mg Penicillin Arm 2 | Measurement of Total and Unbound Penicillin-V Concentration | Unbound penicillin concentration (mg/L) - penicillin alone | 0.56 mg/L | Standard Deviation 0.01 |
| 250mg Penicillin Arm 2 | Measurement of Total and Unbound Penicillin-V Concentration | Total penicillin concentration (mg/L) - penicillin alone | 2.8 mg/L | Standard Deviation 0.1 |
| 250mg Penicillin Arm 2 | Measurement of Total and Unbound Penicillin-V Concentration | Unbound penicillin concentration (mg/L) - penicillin plus probenecid | 1.74 mg/L | Standard Deviation 0.14 |
| 500mg Penicillin Arm 1 | Measurement of Total and Unbound Penicillin-V Concentration | Unbound penicillin concentration (mg/L) - penicillin plus probenecid | 2.36 mg/L | Standard Deviation 0.59 |
| 500mg Penicillin Arm 1 | Measurement of Total and Unbound Penicillin-V Concentration | Total penicillin concentration (mg/L) - penicillin plus probenecid | 10.88 mg/L | Standard Deviation 2.41 |
| 500mg Penicillin Arm 1 | Measurement of Total and Unbound Penicillin-V Concentration | Unbound penicillin concentration (mg/L) - penicillin alone | 0.97 mg/L | Standard Deviation 0.22 |
| 500mg Penicillin Arm 1 | Measurement of Total and Unbound Penicillin-V Concentration | Total penicillin concentration (mg/L) - penicillin alone | 5.03 mg/L | Standard Deviation 1.46 |
| 500mg Penicillin Arm 2 | Measurement of Total and Unbound Penicillin-V Concentration | Total penicillin concentration (mg/L) - penicillin alone | 3.62 mg/L | Standard Deviation 1.56 |
| 500mg Penicillin Arm 2 | Measurement of Total and Unbound Penicillin-V Concentration | Unbound penicillin concentration (mg/L) - penicillin plus probenecid | 1.52 mg/L | Standard Deviation 0.76 |
| 500mg Penicillin Arm 2 | Measurement of Total and Unbound Penicillin-V Concentration | Unbound penicillin concentration (mg/L) - penicillin alone | 0.65 mg/L | Standard Deviation 0.27 |
| 500mg Penicillin Arm 2 | Measurement of Total and Unbound Penicillin-V Concentration | Total penicillin concentration (mg/L) - penicillin plus probenecid | 6.50 mg/L | Standard Deviation 3.2 |
| 750mg Penicillin Arm 1 | Measurement of Total and Unbound Penicillin-V Concentration | Total penicillin concentration (mg/L) - penicillin plus probenecid | 12 mg/L | Standard Deviation 2.27 |
| 750mg Penicillin Arm 1 | Measurement of Total and Unbound Penicillin-V Concentration | Unbound penicillin concentration (mg/L) - penicillin plus probenecid | 2.63 mg/L | Standard Deviation 0.64 |
| 750mg Penicillin Arm 1 | Measurement of Total and Unbound Penicillin-V Concentration | Unbound penicillin concentration (mg/L) - penicillin alone | 1.22 mg/L | Standard Deviation 0.34 |
| 750mg Penicillin Arm 1 | Measurement of Total and Unbound Penicillin-V Concentration | Total penicillin concentration (mg/L) - penicillin alone | 6.53 mg/L | Standard Deviation 5.38 |
| 750mg Penicillin Arm 2 | Measurement of Total and Unbound Penicillin-V Concentration | Unbound penicillin concentration (mg/L) - penicillin alone | 1.08 mg/L | Standard Deviation 0.15 |
| 750mg Penicillin Arm 2 | Measurement of Total and Unbound Penicillin-V Concentration | Total penicillin concentration (mg/L) - penicillin plus probenecid | 12 mg/L | Standard Deviation 3 |
| 750mg Penicillin Arm 2 | Measurement of Total and Unbound Penicillin-V Concentration | Unbound penicillin concentration (mg/L) - penicillin plus probenecid | 2.84 mg/L | Standard Deviation 0.77 |
| 750mg Penicillin Arm 2 | Measurement of Total and Unbound Penicillin-V Concentration | Total penicillin concentration (mg/L) - penicillin alone | 6.2 mg/L | Standard Deviation 0.8 |
Primary
Measurement of Total and Unbound Penicillin-V Concentration
Measurement of blood concentration at 180 minutes post dose with and without probenecid.
Time frame: 180 minutes post an observed dose.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| 250mg Penicillin Arm 1 | Measurement of Total and Unbound Penicillin-V Concentration | Total penicillin concentration (mg/L) - penicillin alone | 0.13 mg/L | Standard Deviation 0.05 |
| 250mg Penicillin Arm 1 | Measurement of Total and Unbound Penicillin-V Concentration | Unbound penicillin concentration (mg/L) - penicillin alone | 0.03 mg/L | Standard Deviation 0.01 |
| 250mg Penicillin Arm 1 | Measurement of Total and Unbound Penicillin-V Concentration | Total penicillin concentration (mg/L) - penicillin plus probenecid | 1.58 mg/L | Standard Deviation 0.87 |
| 250mg Penicillin Arm 1 | Measurement of Total and Unbound Penicillin-V Concentration | Unbound penicillin concentration (mg/L) - penicillin plus probenecid | 0.33 mg/L | Standard Deviation 0.16 |
| 250mg Penicillin Arm 2 | Measurement of Total and Unbound Penicillin-V Concentration | Total penicillin concentration (mg/L) - penicillin plus probenecid | 2.35 mg/L | Standard Deviation 1.15 |
| 250mg Penicillin Arm 2 | Measurement of Total and Unbound Penicillin-V Concentration | Unbound penicillin concentration (mg/L) - penicillin alone | 0.15 mg/L | Standard Deviation 0.07 |
| 250mg Penicillin Arm 2 | Measurement of Total and Unbound Penicillin-V Concentration | Total penicillin concentration (mg/L) - penicillin alone | 0.85 mg/L | Standard Deviation 0.45 |
| 250mg Penicillin Arm 2 | Measurement of Total and Unbound Penicillin-V Concentration | Unbound penicillin concentration (mg/L) - penicillin plus probenecid | 0.49 mg/L | Standard Deviation 0.21 |
| 500mg Penicillin Arm 1 | Measurement of Total and Unbound Penicillin-V Concentration | Unbound penicillin concentration (mg/L) - penicillin plus probenecid | 1.18 mg/L | Standard Deviation 0.51 |
| 500mg Penicillin Arm 1 | Measurement of Total and Unbound Penicillin-V Concentration | Total penicillin concentration (mg/L) - penicillin plus probenecid | 5.18 mg/L | Standard Deviation 2.15 |
| 500mg Penicillin Arm 1 | Measurement of Total and Unbound Penicillin-V Concentration | Unbound penicillin concentration (mg/L) - penicillin alone | 0.18 mg/L | Standard Deviation 0.14 |
| 500mg Penicillin Arm 1 | Measurement of Total and Unbound Penicillin-V Concentration | Total penicillin concentration (mg/L) - penicillin alone | 0.98 mg/L | Standard Deviation 0.76 |
| 500mg Penicillin Arm 2 | Measurement of Total and Unbound Penicillin-V Concentration | Total penicillin concentration (mg/L) - penicillin alone | 0.85 mg/L | Standard Deviation 0.26 |
| 500mg Penicillin Arm 2 | Measurement of Total and Unbound Penicillin-V Concentration | Unbound penicillin concentration (mg/L) - penicillin plus probenecid | 0.49 mg/L | Standard Deviation 0.11 |
| 500mg Penicillin Arm 2 | Measurement of Total and Unbound Penicillin-V Concentration | Unbound penicillin concentration (mg/L) - penicillin alone | 0.16 mg/L | Standard Deviation 0.05 |
| 500mg Penicillin Arm 2 | Measurement of Total and Unbound Penicillin-V Concentration | Total penicillin concentration (mg/L) - penicillin plus probenecid | 2.22 mg/L | Standard Deviation 0.56 |
| 750mg Penicillin Arm 1 | Measurement of Total and Unbound Penicillin-V Concentration | Total penicillin concentration (mg/L) - penicillin plus probenecid | 6.67 mg/L | Standard Deviation 3.09 |
| 750mg Penicillin Arm 1 | Measurement of Total and Unbound Penicillin-V Concentration | Unbound penicillin concentration (mg/L) - penicillin plus probenecid | 1.46 mg/L | Standard Deviation 0.78 |
| 750mg Penicillin Arm 1 | Measurement of Total and Unbound Penicillin-V Concentration | Unbound penicillin concentration (mg/L) - penicillin alone | 0.35 mg/L | Standard Deviation 0.13 |
| 750mg Penicillin Arm 1 | Measurement of Total and Unbound Penicillin-V Concentration | Total penicillin concentration (mg/L) - penicillin alone | 1.97 mg/L | Standard Deviation 0.76 |
| 750mg Penicillin Arm 2 | Measurement of Total and Unbound Penicillin-V Concentration | Unbound penicillin concentration (mg/L) - penicillin alone | 0.09 mg/L | Standard Deviation 0.03 |
| 750mg Penicillin Arm 2 | Measurement of Total and Unbound Penicillin-V Concentration | Total penicillin concentration (mg/L) - penicillin plus probenecid | 3.55 mg/L | Standard Deviation 1.45 |
| 750mg Penicillin Arm 2 | Measurement of Total and Unbound Penicillin-V Concentration | Unbound penicillin concentration (mg/L) - penicillin plus probenecid | 0.81 mg/L | Standard Deviation 0.34 |
| 750mg Penicillin Arm 2 | Measurement of Total and Unbound Penicillin-V Concentration | Total penicillin concentration (mg/L) - penicillin alone | 0.45 mg/L | Standard Deviation 0.15 |
Secondary
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.
Time frame: 45 minutes post an observed dose.
Population: All 20 participants received the same dose (500mg QDS) of probenecid regardless of study arm. Results are therefore presented for all participants for this outcome.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 250mg Penicillin Arm 1 | Measurement of Total and Unbound Probenecid Concentration | 79.0 mg/L | Standard Deviation 21.4 |
| 250mg Penicillin Arm 2 | Measurement of Total and Unbound Probenecid Concentration | 6.6 mg/L | Standard Deviation 1.5 |
Secondary
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.
Time frame: 180 minutes post an observed dose.
Population: All 20 participants received the same dose (500mg QDS) of probenecid regardless of study arm. Results are therefore presented for all participants for this outcome.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 250mg Penicillin Arm 1 | Measurement of Total and Unbound Probenecid Concentration | 81.1 mg/L | Standard Deviation 20.6 |
| 250mg Penicillin Arm 2 | Measurement of Total and Unbound Probenecid Concentration | 6.6 mg/L | Standard Deviation 1.5 |