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Trial registered on ANZCTR


Registration number
ACTRN12617001003369
Ethics application status
Approved
Date submitted
9/07/2017
Date registered
12/07/2017
Date last updated
12/07/2017
Type of registration
Retrospectively registered

Titles & IDs
Public title
Probenecid and food effects on flucloxacillin pharmacokinetics and pharmacodynamics in healthy volunteers
Scientific title
Probenecid and food effects on flucloxacillin pharmacokinetics and pharmacodynamics in healthy volunteers
Secondary ID [1] 292389 0
None
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Skin infection 303981 0
Condition category
Condition code
Infection 303308 303308 0 0
Other infectious diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Volunteers were administered flucloxacillin 1000 mg orally on three study days separated by a 7-day ‘washout period’.
Arm 1: Flucloxacillin 1000 mg orally, single dose while fasting
Arm 2: Flucloxacillin 1000 mg orally plus probenecid 500 mg orally, both single dose while fasting
Arm 3: Flucloxacillin 1000 mg orally plus probenecid 500 mg orally, both single dose with food
On each study day, participants fasted for eight hours (overnight) but had free access to water. On fasting days only water could be consumed until two hours after receiving the study medication. On the fed day, each participant ingested two scrambled eggs made with two tablespoons of milk (full cream), two slices of mixed grain and toasted sesame bread with margarine and 250 mL of orange juice. Each meal contained 492 kcal of energy, 21.8 g of protein, 22 g of fat and 52.6 g of carbohydrate. Caffeine was permitted only after the 4-hour blood sample, and alcohol was forbidden until completion of the study. Adherence to fasting was assessed verbally.
Intervention code [1] 298563 0
Treatment: Drugs
Comparator / control treatment
Arm 1: Flucloxacillin 1000 mg orally, single dose while fasting
Control group
Active

Outcomes
Primary outcome [1] 302692 0
Total flucloxacillin plasma concentrations were measured using an LC-MS/MS method
Timepoint [1] 302692 0
Blood samples were taken at baseline then 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8 and 12 hours after administration of flucloxacillin
Primary outcome [2] 302718 0
Free flucloxacillin plasma concentrations were measured using an LC-MS/MS method
Timepoint [2] 302718 0
Blood samples were taken at baseline then 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8 and 12 hours after administration of flucloxacillin
Secondary outcome [1] 336770 0
Adverse events, such as nausea, anorexia, diarrhoea, skin itch or rash were assessed by verbal questioning at the end of each study day
Timepoint [1] 336770 0
0 to 12 hours after administration of study drugs

Eligibility
Key inclusion criteria
Healthy volunteer
Minimum age
18 Years
Maximum age
40 Years
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
Food intolerance, pregnancy, chronic illness, renal impairment (creatinine clearance < 80 mL/min by Cockcroft-Gault formula), liver dysfunction, malabsorption or known intolerance of flucloxacillin or probenecid. Volunteers were excluded from the study if they took any regular medications (other than a hormonal oral contraceptive pill) or were intolerant of fasting for up to 10 hours.

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Crossover
Other design features
Phase
Phase 1
Type of endpoint/s
Pharmacokinetics
Statistical methods / analysis
The number of volunteers chosen was pretty standard for a PK/PD study of this type. Treatment arms were compared for common PK parameters and for the concentrations achieved for 30%, 50% and 70% of the usual dose intervals. Statistics evaluated included repeated measures one-way ANOVA, ratios of each regimen over the others, post-hoc analysis using Bonferroni’s multiple comparison test, and if no differences were demonstrated, 90% confidence intervals for bioequivalence testing (mean ± 90% CI within 0.8 to 1.25). The probability of target attainment (PTAs) for each arm were plotted against a range of MICs of common skin-infecting bacteria

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
Actual
7/01/2013
Date of last participant enrolment
Anticipated
Actual
11/02/2013
Date of last data collection
Anticipated
Actual
11/02/2013
Sample size
Target
11
Accrual to date
Final
11
Recruitment outside Australia
Country [1] 9041 0
New Zealand
State/province [1] 9041 0
Nelson/Tasman

Funding & Sponsors
Funding source category [1] 296944 0
Other
Name [1] 296944 0
Nelson Research and Education Trust Fund
Country [1] 296944 0
New Zealand
Primary sponsor type
Individual
Name
Richard Everts
Address
Department of Medicine
Nelson Hospital
Private Bag 18
Nelson 7042
Country
New Zealand
Secondary sponsor category [1] 295947 0
None
Name [1] 295947 0
Address [1] 295947 0
Country [1] 295947 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 298149 0
Northern B Health and Disability Ethics Committee
Ethics committee address [1] 298149 0
Ministry of Health
Health and Disability Ethics Committees
PO Box 5013
Wellington 6140
Ethics committee country [1] 298149 0
New Zealand
Date submitted for ethics approval [1] 298149 0
05/11/2012
Approval date [1] 298149 0
27/11/2012
Ethics approval number [1] 298149 0
12/NTB/56

Summary
Brief summary
Introduction and methods
Flucloxacillin is the first-line antibiotic agent in many parts of the world, including NZ and Australia, for treating Staphylococcus aureus and skin infections. It is often given by 24-hour intravenous (IV) infusion to outpatients with moderately severe infections, but this costs NZ$150-200/day and sometimes causes problems with the IV catheter. It is often given by mouth to patients with mild infections, but this requires four-times-daily dosing and is recommended to be taken 1 hour before or 2 hours after a meal. It would be very useful if there was a more effective and convenient oral flucloxacillin regimen that could be taken with or without food.
In the early 1950s, probenecid was developed as a penicillin ‘booster’. In this study, we evaluated the effect of low dose probenecid (500 mg), with or without a small meal, on oral flucloxacillin pharmacokinetics in 11 healthy volunteers. We used modern testing methods, measured free flucloxacillin concentrations, and evaluated the results in terms of modern PK/PD targets for the likely bacteria involved.

Results
Probenecid delayed clearance of flucloxacillin from the body, approximately doubling the time the flucloxacillin was above the target minimum inhibitory concentration (MIC90 = 0.5 mg/L for Staphylococcus aureus. Food delayed the absorption of flucloxacillin but did not reduce it.. For a target of time above 0.5 mg/L for more than 50% of the day (e.g. for a deep S. aureus bone or joint infection), modeling at steady state showed that flucloxacillin 1 g with probenecid 500 mg taken 6- or 8-hourly with or without food would achieve this in almost all cases. For a target of time above 0.5 mg/L for more than 30% of the day (e.g. for a mild skin infection), modeling at steady state showed that flucloxacillin 1 g with probenecid 500 mg taken twice daily with or without food would achieve this in almost all cases.

Conclusion
These results show that probenecid is a powerful booster of flucloxacillin and that food did not negatively affect the relevant results. Taking probenecid and flucloxacillin together could enable patients with mild infections to have a more convenient twice daily regimen and could enable patients with moderate deep serious gram-positive infections to avoid home intravenous infusions.
Trial website
Trial related presentations / publications
A report of this work was presented verbally at the Australasian Society of Clinical and Experimental Pharmacologists and Toxicologists (ASCEPT) annual scientific meeting in Melbourne, Australia, in December 2013 and at the Australasian Society for Infectious Diseases (ASID) annual scientific meeting in Adelaide, Australia, in March 2014. Abstracts were not published for non-attendees.
Public notes
Attachments [1] 1873 1873 0 0
/AnzctrAttachments/369309-12-NTB-56_Approved_Letter.pdf (Ethics approval)
Attachments [2] 1874 1874 0 0
/AnzctrAttachments/369309-probenecid flucloxacillin PK in volunteers study - protocol.doc (Protocol)
Attachments [3] 1875 1875 0 0
/AnzctrAttachments/369309-Abstract ASID March 2014 - Everts et al - Flucloxacillin and Probenecid.docx (Publication)

Contacts
Principal investigator
Name 60294 0
Dr Richard Everts
Address 60294 0
Department of Medicine
Nelson Hospital
Private Bag 18
Nelson 7042
Country 60294 0
New Zealand
Phone 60294 0
+64 3 539-1170
Fax 60294 0
+64 3 539-4958
Email 60294 0
richard.everts@nbph.org.nz
Contact person for public queries
Name 60295 0
Dr Richard Everts
Address 60295 0
Department of Medicine
Nelson Hospital
Private Bag 18
Nelson 7042
Country 60295 0
New Zealand
Phone 60295 0
+64 3 539-1170
Fax 60295 0
+64 3 539-4958
Email 60295 0
richard.everts@nbph.org.nz
Contact person for scientific queries
Name 60296 0
Dr Richard Everts
Address 60296 0
Department of Medicine
Nelson Hospital
Private Bag 18
Nelson 7042
Country 60296 0
New Zealand
Phone 60296 0
+64 3 539-1170
Fax 60296 0
+64 3 539-4958
Email 60296 0
richard.everts@nbph.org.nz

No information has been provided regarding IPD availability


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
SourceTitleYear of PublicationDOI
EmbaseProbenecid and food effects on flucloxacillin pharmacokinetics and pharmacodynamics in healthy volunteers.2020https://dx.doi.org/10.1016/j.jinf.2019.09.004
N.B. These documents automatically identified may not have been verified by the study sponsor.