The primary objective of this study is to evaluate the effect of multiple doses of azithromycin, clarithromycin and ritonavir on the pharmacokinetics, safety and tolerability of a single oral 150 mg dose of ivacaftor in healthy controls and in…
ID
Source
Brief title
Condition
- Chromosomal abnormalities, gene alterations and gene variants
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The principal outcome variable is the ratio (RAUC) of total area under the
plasma concentration curve (AUC) for oral ivacaftor during co-administration of
inhibitor (AUCI : ritonavir, clarithromycin and azithromycin) divided by the
AUC in the control condition with no inhibitor (AUC0) :
RAUC = (AUCI)/(AUC0)
Secondary outcome
Number of adverse and serious adverse events
The maximum observed plasma concentration (Cmax), the time to achieve Cmax
(Tmax), the mean terminal half-life of ivacaftor.
Other study parameters
* Age
* Gender
* Height
* Weight
* Pregnancy test (if applicable)
Background summary
Most therapies for cystic fibrosis (CF) are mainly symptomatic. However,
multiple compounds have been identified recently that target mutation-specific
defects of the CFTR (Cystic fibrosis transmembrane conductance regulator)
protein, including potentiators that enhance the CFTR channel gating and
correctors that correct CFTR misprocessing. The potentiatior *ivacaftor* has
been FDA- and EMA approved for CF patients carrying a CFTR class III mutation
based on an impressive clinical improvement. Ongoing trials examine the safety
and efficacy of ivacaftor and combination of corrector/potentiator drugs in
several other CFTR mutations. Ivacaftor is mainly metabolized by cytochrome
P450 3A4. As patients with CF are often treated with drugs that inhibit the
activity of cytochrome P450 3A4 there is need for information on the
interaction between ivacaftor and these drugs in relation to serum drug levels.
With this study we will investigate the efficacy and safety of co-
administration of CYP3A4 inhibitors and ivacaftor in healthy controls and CF
patients.
Study objective
The primary objective of this study is to evaluate the effect of multiple doses
of azithromycin, clarithromycin and ritonavir on the pharmacokinetics, safety
and tolerability of a single oral 150 mg dose of ivacaftor in healthy controls
and in cystic fibrosis patients.
Secondary Objectives are to:
-Calculate an optimal dosing scheme for ivacaftor therapy in cystic fibrosis
patients when it is co-administered with a weak, strong and very strong CYP3A
inhibitor.
-Compare the results of healthy controls and cystic fibrosis patients.
Study design
a single center open label intervention study.
Intervention
In phase 2, all subjects will receive a single dose of oral ivacaftor. In phase
3, all subjects will receive 7 doses of oral ritonavir an 1 dose of oral
ivacaftor. In phase 4, all subjects will receive 5 doses of oral clarithromycin
and 1 dose of oral ivacaftor. In phase 5, all subjects will receive 3 doses of
oral azithromycin and 1 dose of oral ivacaftor.
Study burden and risks
Patients participating in this study will be treated at home. Patients will
visit the hospital for 4 study visits. At time points 24, 48, 72 hours a member
of our research team will visit the patient at home in order to collect blood
by a venapunction (10 times in total). During the 4 hospital visits a
peripheral venous catheter will be placed in order to collect 7 blood samples.
Ivacaftor and the CYP3A4 inhibitors are all registered drugs and the dose we
prescribe does not exceed the registered dose. Therefore we do not expect
serious problems or side effects during this study.
CYP3A4 inhibitors are often prescribed to our cystic fibrosis patients in daily
practice. Most studies on ivacaftor excluded patients using this medication. In
order to prescribe this very important drug to CF patients using a CYP3A4
inhibitor this study is needed to give a founded dosage advice regarding safety
issues and efficacy
Els Borst-Eilersplein 275 nvt
2545 AA Den Haag nvt
NL
Els Borst-Eilersplein 275 nvt
2545 AA Den Haag nvt
NL
Listed location countries
Age
Inclusion criteria
Inclusion criteria for Healthy controls
-Males and females, aged 18 years or older on the date of informed consent
-No medical history and no medication
-Signed informed consent form (ICF)
- Able to understand and comply with protocol requirements, restrictions, and instructions, and likely to complete the study as planned, as judged by the investigator.;Inclusion criteria for Cystic Fibrosis patients
-Males and females, aged 18 years or older on the date of informed consent
-Cystic fibrosis (confirmed by genotype analysis, Class 1 and 2)
-Exocrine pancreatic insufficiency
-Signed informed consent form (ICF)
- Able to understand and comply with protocol requirements, restrictions, and instructions, and likely to complete the study as planned, as judged by the investigator
Exclusion criteria
For both healthy controls as CF-patients the following exclusion criteria apply:
- Use of ivacaftor
- History of clinically significant cirrhosis with or without portal hypertension.
- Severe renal impairment (creatinine clearance * 30 ml/min);
- Use of drugs that are metabolized by the CYP3A enzyme or have a known influence on the CYP3A enzyme (inducers or inhibitors): see appendix.
- Known allergy/intolerance to clarithromycin, ritonavir or azithromycin
- Pregnancy or lactation
- Pregnancy wish
- Pulmonary exacerbation with hospital admission within one month before the study period (defined as need for intravenous antibiotics) ;For the Healthy controls an extra Exclusion Criterium applies:
- Blood relationship in the first or second degree with a CF-patient
Design
Recruitment
Medical products/devices used
metc-ldd@lumc.nl
metc-ldd@lumc.nl
metc-ldd@lumc.nl
Followed up by the following (possibly more current) registration
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In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2016-001440-18-NL |
| CCMO | NL58561.098.17 |