Clinical trial NCT02440841: Study in Healthy Male Subjects to Evaluate the Effect of Itraconazole and Rifampicin on the PK of Fedovapagon
Official title: Single Center, Open-Label, Single-Sequence, Within-Subject Study In Two Cohorts Of Healthy Male Subjects Comparing Single-Dose Pharmacokinetics Of Fedovapagon Alone And In Combination With A CYP3A4 Inhibitor, Itraconazole, Or A CYP3A4 Inducer, Rifampicin
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Nocturia
Keywords: VA106483
fedovapagon
drug-drug interaction
DDI
males
rifampicin
rifampin
itraconazole
CYP3A4
pharmacokinetics
PK
Lead sponsor: Vantia Ltd
Sponsor class: INDUSTRY
First posted: 2015-05-12
Enrollment: 29
Sex: MALE
Minimum age (years): 18
Maximum age (years): 45
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to investigate the potential for co-administration of strong inhibitors or inducers of CYP3A4 to alter the pharmacokinetics of fedovapagon.

Detailed description: Fedovapagon is a vasopressin V2 receptor agonist in development for the treatment of nocturia. Agonism of the V2 receptor, located in the collecting ducts of the kidney, leads to translocation of aquaporin channels and increased re absorption of water and anti-diuresis.

A number of drugs that are commonly co-prescribed in the population who may present for treatment of nocturia are inhibitors of CYP3A4, including diltiazem, verapamil, erythromycin and clarithromycin and may therefore impact the plasma levels of fedovapagon if co administered.

Conversely, concomitant intake of drugs that are potent CYP3A4 inducers may lead to lower than anticipated plasma concentrations of fedovapagon thus reducing the efficacy of fedovapagon. It is therefore important to assess the effect of CYP3A4 induction on the pharmacokinetic (PK) parameters of fedovapagon.

The study design uses itraconazole as a potent inhibitor of CYP3A4 and, in a separate cohort of subjects, rifampicin as a potent CYP3A4 inducer at doses intended to maximize the potential to demonstrate an interaction.

Eligibility criteria: Inclusion Criteria:

* Healthy males aged 18 to 45
* Have a body mass index between 18 and 29.9 kg/m2 (weight: ≥50 kg and ≤100 kg)
* No clinically significant medical history
* Ability to comply with the requirements of the study
* Provide written informed consent
* Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) should be below or equal to upper level of normal (ULN). Otherwise liver enzymes should show no clinical significant abnormalities. Total bilirubin should not exceed 1.5 x ULN. Liver enzymes will be re-tested only once before randomization if required.
* Be judged by the Investigator to be in good health based on medical history (in particular, no congestive heart failure, ischemic heart disease, valvular heart disease, significant pulmonary disease, renal failure, edematous disorder, liver disease, gastric disorders, porphyria, diabetes mellitus or hereditary disorders of carbohydrate metabolism), physical examination, vital sign measurements and laboratory safety tests
* Agree to refrain from the consumption of grapefruit or grapefruit juice, apple or orange juice, vegetables from the mustard green family (e.g., kale, broccoli, watercress, collard greens, kohlrabi, brussels sprouts, mustard) and charbroiled meats containing products beginning 1 week prior to administration of the initial administration of trial drug, throughout the trial
* Use of any prescribed medication or St John's Wort within 14 days (or 5 half-lives if this is longer) or over-the-counter medication (except paracetamol) within 1 week of dosing. Specific medication not to be taken within 2 weeks of (before or after) administration of itraconazole is described in the Summary of Product Characteristic for Sempera®

Primary outcomes:
measure: Plasma fedovapagon concentration in presence and absence of co-administered itraconazole or rifampicin
timeFrame: 10-12 days
Secondary outcomes:
measure: Maximum observed plasma concentration (Cmax)
timeFrame: 10-12 days
measure: Area under the plasma concentration curve versus time curve with extrapolation to infinity (AUC(0-infinity))
timeFrame: 10-12 days
measure: Number and type of adverse events
timeFrame: 12-14 days
measure: Change from baseline in 12-lead ECG
timeFrame: 12-14 days
measure: Change from baseline in vital signs and physical examination
timeFrame: 12-14 days
measure: Change from baseline in laboratory assessments
timeFrame: 12-14 days
Other outcomes:
Locations:
city: Berlin
country: Germany
facility: PAREXEL Early Phase Clinical Unit Berlin
Study officials:
affiliation: Parexel
name: Tshibuabua Kabasela
role: STUDY_DIRECTOR
References: