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Trial registered on ANZCTR


Registration number
ACTRN12617001046392
Ethics application status
Approved
Date submitted
15/07/2017
Date registered
18/07/2017
Date last updated
18/07/2017
Type of registration
Retrospectively registered

Titles & IDs
Public title
Effect of food on oral flucloxacillin pharmacokinetics and pharmacodynamics in healthy volunteers
Scientific title
Effect of food on oral flucloxacillin pharmacokinetics and pharmacodynamics in healthy volunteers
Secondary ID [1] 292437 0
None
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Skin infection 304043 0
Condition category
Condition code
Infection 303368 303368 0 0
Other infectious diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Volunteers received flucloxacillin 1000 mg orally on an empty stomach or after a standardized high-fat high-calorie breakfast (per FDA recommendations for bioequivalence studies ie. equating to ~968 kcal of energy, 38 g of protein, 65 g of fat and 58 g of carbohydrate) after an 8 hour overnight fast (free access to water during this time) on two study days separated by a 7-day 'washout period'.

Intervention code [1] 298615 0
Treatment: Drugs
Comparator / control treatment
Flucloxacillin 1000 mg orally, administered in the fasting state (current recommended practice).
Control group
Active

Outcomes
Primary outcome [1] 302759 0
.Total flucloxacillin plasma concentrations were measured using a published LC-MS/MS method.
Timepoint [1] 302759 0
Blood samples were taken at 0, 0.5, 1.5, 2, 3, 4, 6, 8 and 12 hours post dose for determination of total and free flucloxacillin plasma concentrations
Primary outcome [2] 302771 0
Free flucloxacillin concentrations measured using a published LC-MS/MS method.
Timepoint [2] 302771 0
Blood samples were taken at 0, 0.5, 1.5, 2, 3, 4, 6, 8 and 12 hours post dose for determination of total and free flucloxacillin plasma concentrations
Secondary outcome [1] 336916 0
Flucloxacillin concentrations in urine were measured using LC-MS/MS.
Timepoint [1] 336916 0
Urine was collected from 0 - 12 hours post-dose to determine the total flucloxacillin urinary excretion.

Eligibility
Key inclusion criteria
Healthy volunteers
Minimum age
18 Years
Maximum age
40 Years
Gender
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. 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
Other design features
Phase
Phase 3
Type of endpoint(s)
Pharmacokinetics / pharmacodynamics
Statistical methods / analysis
The number of volunteers chosen was standard for a PK/PD study of this type (n=12). Treatment arms were compared for common PK parameters and for the free concentrations achieved for 30%, 50% and 70% of the usual dose intervals. Statistical analysis was undertaken using Graphpad Prism (student t-test and bioequivalence testing if no difference was identified). Modelling was undertaken using Monolix to predict steady-state pharmacokinetics. 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
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment outside Australia
Country [1] 9058 0
New Zealand
State/province [1] 9058 0

Funding & Sponsors
Funding source category [1] 296997 0
Charities/Societies/Foundations
Name [1] 296997 0
New Zealand Pharmacy & Education Research Foundation
Address [1] 296997 0
Po Box 11640
Manners Street
Wellington 6142
Country [1] 296997 0
New Zealand
Primary sponsor type
Hospital
Name
Canterbury District Health Board (Christchurch Hospital campus)
Address
PO Box 4170
Christchurch 8140
Country
New Zealand
Secondary sponsor category [1] 296002 0
University
Name [1] 296002 0
University of Otago, Christchurch
Address [1] 296002 0
Private Bag 4345
Christchurch 8140
New Zealand
Country [1] 296002 0
New Zealand

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 298193 0
Northern B Health & Disability Ethics Committee
Ethics committee address [1] 298193 0
Ministry of Health
Health and Disability Ethics Committees
PO Box 5013
Wellington 6140
Ethics committee country [1] 298193 0
New Zealand
Date submitted for ethics approval [1] 298193 0
23/12/2013
Approval date [1] 298193 0
21/02/2014
Ethics approval number [1] 298193 0
12/NTB/56

Summary
Brief summary
Flucloxacillin is usually recommended to be given on an empty stomach, because food reduces and delays peak concentrations. It is now known that for penicillins, the time the free (unbound) concentrations are above the minimum inhibitory concentrations is more important for bacterial kill than peak concentrations. In this study, the effects of food on flucloxacillin PK-PD were assess using a modern assay to accurately quantify free flucloxacillin concentrations. Total and free flucloxacillin concentrations were measured for 12 hours after a single oral dose of flucloxacillin 1000 mg, after a standardized breakfast and in a fasting state separated by a week's washout.
Pharmacokinetics and pharmacodynamics were compared in the fed and fasting states.
Food reduced the total and free flucloxacillin area under the curve by about 20%, and the peak by about 50%, and increased the time to reach peak concentrations by approximately 2-fold. These changes did not importantly impact on parameters such as free time above MIC and probability of target attainment suggesting that flucloxacillin can be taken with food without compromising efficacy in most cases.
Trial website
Trial related presentations / publications
This work has been included in a presentation at the New Zealand Hospital Pharmacists Association in Christchurch, New Zealand (November 2013). This has been published in the conference handbook (not official conference proceedings) i.e. SJ Gardiner 'Preserving our Licence to Kill - three years in the life of an antimicrobial stewardship pharmacist', New Zealand Hospital Pharmacists Association, Christchurch, New Zealand 2016.
Public notes

Contacts
Principal investigator
Name 76286 0
Dr Sharon Gardiner
Address 76286 0
C/- Infectious Diseases
Christchurch Hospital
PO Box 4710
Christchurch 8140
Country 76286 0
New Zealand
Phone 76286 0
+6433640084
Fax 76286 0
Email 76286 0
sharon.gardiner@cdhb.health.nz
Contact person for public queries
Name 76287 0
Dr Sharon Gardiner
Address 76287 0
C/0 Infectious Diseases
Po Box 4710
Christchurch 8140
Country 76287 0
New Zealand
Phone 76287 0
+6433640084
Fax 76287 0
Email 76287 0
Sharon.gardiner@cdhb.health.nz
Contact person for scientific queries
Name 76288 0
Dr Sharon Gardiner
Address 76288 0
C/- Infectious Diseases
Christchurch Hospital
PO Box 4710
Christchurch
Country 76288 0
New Zealand
Phone 76288 0
+6433640084
Fax 76288 0
Email 76288 0
sharon.gardiner@cdhb.health.nz

No information has been provided regarding IPD availability
Summary results
Have study results been published in a peer-reviewed journal?
Other publications
Have study results been made publicly available in another format?
Results – basic reporting
Results – plain English summary