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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]

None

Universal Trial Number (UTN)

Trial acronym

Linked study record

Health condition

Health condition(s) or problem(s) studied:

Skin infection

Condition category

Condition code

Infection

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]

Treatment: Drugs

Comparator / control treatment

Arm 1: Flucloxacillin 1000 mg orally, single dose while fasting

Control group

Active

Outcomes

Primary outcome [1]

Total flucloxacillin plasma concentrations were measured using an LC-MS/MS method

Timepoint [1]

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]

Free flucloxacillin plasma concentrations were measured using an LC-MS/MS method

Timepoint [2]

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]

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]

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

Accrual to date

Final

Recruitment outside Australia

Country [1]

New Zealand

State/province [1]

Nelson/Tasman

Funding & Sponsors

Funding source category [1]

Other

Name [1]

Nelson Research and Education Trust Fund

Address [1]

c/o Dr Bruce King
Nelson Hospital
Private Bag 18
Nelson 7042

Country [1]

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]

None

Name [1]

Address [1]

Country [1]

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

Northern B Health and Disability Ethics Committee

Ethics committee address [1]

Ministry of Health
Health and Disability Ethics Committees
PO Box 5013
Wellington 6140

Ethics committee country [1]

New Zealand

Date submitted for ethics approval [1]

05/11/2012

Approval date [1]

27/11/2012

Ethics approval number [1]

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]

/AnzctrAttachments/369309-12-NTB-56_Approved_Letter.pdf (Ethics approval)

Attachments [2]

/AnzctrAttachments/369309-probenecid flucloxacillin PK in volunteers study - protocol.doc (Protocol)

Attachments [3]

/AnzctrAttachments/369309-Abstract ASID March 2014 - Everts et al - Flucloxacillin and Probenecid.docx (Publication)

Contacts

Principal investigator

Name

Dr Richard Everts

Address

Department of Medicine
Nelson Hospital
Private Bag 18
Nelson 7042

Country

New Zealand

Phone

+64 3 539-1170

Fax

+64 3 539-4958

richard.everts@nbph.org.nz

Contact person for public queries

Name

Richard Everts

Address

Department of Medicine
Nelson Hospital
Private Bag 18
Nelson 7042

Country

New Zealand

Phone

+64 3 539-1170

Fax

+64 3 539-4958

richard.everts@nbph.org.nz

Contact person for scientific queries

Name

Richard Everts

Address

Department of Medicine
Nelson Hospital
Private Bag 18
Nelson 7042

Country

New Zealand

Phone

+64 3 539-1170

Fax

+64 3 539-4958

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

Source	Title	Year of Publication	DOI
Embase	Probenecid and food effects on flucloxacillin pharmacokinetics and pharmacodynamics in healthy volunteers.	2020	https://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.

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Documents added automatically