To investigate the influence of flucloxacillin treatment on CYP - and UGT substrate plasma concentration, to gain further understanding of potential clinically relevant drug-drug interactions with flucloxacillin.
ID
Source
Brief title
Condition
- Bacterial infectious disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Endpoint:
The main study endpoint is the difference in AUC of each substrate drug
(diclofenac, metoprolol, oxycodone, pantoprazole and paracetamol) between day
1/2 and day 10 (+/- 3 days) of flucloxacillin treatment.
Parameter:
Total substrate drug plasma concentration at specific time points (see section
7.3: study procedures).
Secondary outcome
Endpoints:
- Difference in trough concentration of the substrate drugs between day 1/2 and
day 10 (+/- 3 days) of flucloxacillin treatment.
- Difference in trough concentration of substrate drug metabolites (4-OH
diclofenac, alfa-OH-metoprolol, oxymorfon, noroxycodone, pantoprazole-sulfone,
paracetamol-glucuronide) between day 1 and day 10 of flucloxacillin treatment.
- Difference in AUC of substrate drug metabolites between day 1/2 and day 10
(+/- 3 days) of flucloxacillin treatment.
- Difference in the ratio of the AUC of the substrate drugs and their
metabolites between day 1/2 and day 10 (+/- 3 days) of flucloxacillin
treatment.
- Difference in the ratio of the trough concentration of the substrate drugs
and their metabolites between day 1/2 and day 10 (+/- 3 days) of flucloxacillin
treatment.
- Difference in substrate drug dose between day 1/2 and day 10 (+/- 3 days) of
flucloxacillin treatment.
- Subgroup analysis of the above mentioned primary and secondary endpoints in
groups of patients with specific CYP2C9 -, CYP2D6 -, CYP2C19 -, UGT1A1 - and
UGT1A9 phenotypes (see supplementary material S2, table S2 for detailed
information about the genotypes and corresponding phenotypes).
Parameters
CYP2C9 -, CYP2D6 -, CYP2C19 -, UGT1A1 - and UGT1A9 genotypes
Gender
Height
Indication flucloxacillin treatment
Substrate drug metabolite concentration in samples 1-3 at day 1/2 and day 10
(+/- 3 days) of flucloxacillin treatment (see section 7.3 *study procedures*).
Age
Weight
Co-morbidities
Co-medication (incl. dose)
Flucloxacillin dose
Substrate drug dose
Total and unbound serum flucloxacillin concentration
Unbound serum diclofenac and pantoprazole concentration
Plasma creatinine
Plasma ureum
eGFR (CKD-EPI)
Plasma CRP
Plasma albumin
Optional: plasma alpha-1-acid glycoprotein5
Plasma AST
Plasma ALT
Plasma ALP
Plasma GGT
Plasma Bilirubin
Plasma LD
Plasma triglyceride
Background summary
Several studies have reported altered pharmacokinetics - and pharmacodynamics
of multiple drugs in patients that are concomitantly treated with
flucloxacillin. As a result, these patients may suffer from suboptimal plasma
concentrations. To date, the degree and mechanism of these potential drug-drug
interactions with flucloxacillin are unknown. To better understand the clinical
relevance of flucloxacillin*s inducing potential, a prospective drug-drug
interaction (DDI) study is needed where the change in plasma concentration of
common-used drugs that are CYP- UGT substrate drugs is investigated.
Study objective
To investigate the influence of flucloxacillin treatment on CYP - and UGT
substrate plasma concentration, to gain further understanding of potential
clinically relevant drug-drug interactions with flucloxacillin.
Study design
Prospective pharmacokinetics study
Study burden and risks
The risks of this study are limited to the risk of blood sampling. Besides
knowledge about at least one CYP - and/or UGT genotype, patients will obtain no
benefit from this study as blood samples will be collected and analysed at a
later moment.
Els Borst-Eilersplein 275
Den Haag 2545 AA
NL
Els Borst-Eilersplein 275
Den Haag 2545 AA
NL
Listed location countries
Age
Inclusion criteria
- Aged >=18 years
- Treated with >=6 grams/24h flucloxacillin iv (or equivalent dose in case of
renal impairment) for an intended duration of at least 10 days.
- Concomitant treatment with at least one of the following substrate drugs at
the moment of patient selection: diclofenac, metoprolol, oxycodone extended
release tablet, pantoprazole or paracetamol.
- Written informed consent.
Exclusion criteria
- Concomitant use of specific CYP-, UGT- and P-gp inducers and inhibitors (see
table S1 in the supplementary material of the study protocol).
- Pregnancy
- Dialysis patients
- Dementia
- IC-admission
Design
Recruitment
metc-ldd@lumc.nl
metc-ldd@lumc.nl
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In other registers
| Register | ID |
|---|---|
| CCMO | NL86382.058.24 |