Primary objective: To determine the effect of obesity (BMI *35 kg/m2) on the pharmacokinetics, including oral bioavailability of fluconazole.Secondary objective: To develop an optimal dosing regimen for obese patients.
ID
Source
Brief title
Condition
- Fungal infectious disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
A farmacokinetic model using Non Linear Mixed Effects Modelling (NONMEM). Model
validation using bootstrap
method or Sampling Importance Resampling (SIR). The final model will be used
for Monte Carlo simulation for multiple-dosing regimens and higher dosages.
Secondary outcome
NA
Background summary
The incidence of obesity (Body Mass Index (BMI) > 30 kg/m2) is increasing
worldwide. Dosing guidelines are based on clinical trials in which obese
subjects are often excluded. Pharmacokinetic studies are necessary to determine
the appropriate dosing regimen for obese patients, as obesity and morbid
obesity are associated with many physiological changes affecting
pharmacokinetics.
There is clear evidence indicating that heavier patients are receiving a
sub-optimal dose of fluconazole if the current guidelines are used (see H1.1
'Background and rationale' of the protocol). Fluconazole is registered for the
treatment of invasive candidiasis and is a drug of first or second choice,
depending on the Candida species. A sub-optimal dose can result in therapy
failure with an increased risk of mortality, so adequate dosing is needed at
start of treatment.
Fluconazole is available as an oral and intravenous formulation. However,
information on bioavailability of the oral form in obese patient and in patient
who had undergone bariatric surgery, is not known.
Therefore it seems prudent to conduct a trial in a cohort of obese patients who
receive fluconazole oral (400 mg, registered dose), followed by an intravenous
dose of 400 mg fluconazole and define the pharmacokinetics, including oral
bioavailability. These will then be compared to the pharmacokinetics in a
normal-weight group. Both groups receive 400 mg fluconazole oral, followed by
400 mg fluconazole intravenous
This study aims to provide clinical information that will be used to determine
an optimal dosing strategy for obese patients thru modeling and simulation.
Study objective
Primary objective: To determine the effect of obesity (BMI *35 kg/m2) on the
pharmacokinetics, including oral bioavailability of fluconazole.
Secondary objective: To develop an optimal dosing regimen for obese patients.
Study design
This is a prospective, open-label, non-randomized, multi-centre trial.
An oral dose of fluconazole (400 mg) followed by an intravenous dose of
fluconazole (400 mg) is administered.
A PK curve is taken from t = 0.25 to 48 hours.
Intervention
Placin a venous cathether for blood sampling.
Administration of an oral dose of fluconazole (400 mg) followed by an
intravenous dose of fluconazole (400 mg) administered according to SPC.
Sampling of a total of 100 ml of blood (including PK Curve, lab values,
hematology)
Study burden and risks
The risk-classification is assessed as negligible to the patient population
receiving study drug at the current regimen. The drug is licensed on the Dutch
market for the 400 mg dosages administered in this trial. The medication will
be administered as two doses, but none of the two groups (1 obese and 1
non-obese) will receive a dose resulting in an exposure that is higher than
studied in the registrations studies. Fluconazole is considered to be safe up
to a dose of 1600 mg. Therefore, there is no attributable risk for the
application of the study protocol to the subjects.
Koekoekslaan 1
Nieuwegein 3430 EM
NL
Koekoekslaan 1
Nieuwegein 3430 EM
NL
Listed location countries
Age
Inclusion criteria
1. Subjects BMI:
a. obese groups: subject must have a BMI *35 kg/m2 at the time of inclusion;
b. non-obese group: subject must have a BMI *18.5 and <30 kg/m2 at the time of inclusion;
2. Subject is at least 18 of age on the day of screening and not older than 65 years of age on the day of dosing;
3. Subject able and willing to sign the Informed Consent before screening evaluations.
4. If a woman, is neither pregnant nor able to become pregnant and is not nursing an infant.;For the non-obese subjects the following additional inclusion criteria applies:;5. Subject is in good age-appropriate health condition as established by medical history, physical examination, electrocardiography, results of biochemistry, hematology and urinalysis testing within 6 weeks prior to study drug administration. Results of biochemistry, hematology and urinalysis testing should be within the laboratory's reference ranges (see Appendix A). If laboratory results are not within the reference ranges, the subject is included based on the investigator*s judgment that the observed deviations are not clinically relevant. This should be clearly recorded.
Exclusion criteria
1. Documented history of sensitivity to fluconazole or similar azole-compound.
2. Documented history of the long QT syndrome (LQTS)
3. History of, or known abuse of drugs, alcohol or solvents (up until a maximum of three months before study drug administration);
4. Use of medication that has known relevant interaction with study drug as determined by the investigator up to 1 weeks prior to study drug administration;
5. Donation of blood or plasma to a blood bank or in a clinical study (except a screening visit) within 4 weeks prior to study drug administration;
6. Blood transfusion within 8 weeks prior to study drug administration;
7. Treatment with the concerning study drug up to 7 days before administration of the study drug;
8. Any other sound medical, psychiatric and/or social reason as determined by the investigator.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2018-002613-35-NL |
| CCMO | NL66611.100.18 |