Clinical trial NCT02495831: Drug Interaction Study of Safinamide and a BCRP Substrate, Diclofenac, Concomitantly Administered to Healthy Volunteers
Official title: Drug Interaction Study of Safinamide and a BCRP Substrate, Diclofenac, Concomitantly Administered to Healthy Volunteers
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Healthy
Keywords: PK study
Lead sponsor: Zambon SpA
Sponsor class: INDUSTRY
Collaborators: name: Cross Research S.A.
First posted: 2015-07-13
Enrollment: 24
Sex: ALL
Minimum age (years): 22
Maximum age (years): 55
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: CROSSOVER

Brief summary: To evaluate if a single dose of safinamide 200 mg has an effect on the pharmacokinetics of diclofenamic acid, concomitantly administered as a single 50 mg diclofenac sodium dose, with respect to 50 mg diclofenac sodium administered alone.

Detailed description: According to Xadago™ SmPC, safinamide may transiently inhibit BCRP, therefore a time interval of 5 h should be kept between dosing of safinamide and medicinal products that are BCRP substrates with a Tmax ≤2 h (e.g. diclofenac, pitavastatin, pravastatin, ciprofloxacin, methotrexate, topotecan or glyburide).

Following a specific request of EMA CHMP, the present interaction study in healthy male and female volunteers was conducted to determine if co-administration of safinamide with a BCRP substrate alters plasma exposure of the BCRP substrate in vivo.

Diclofenac was chosen among the other BCRP substrates considering its large use in the general population. Diclofenac in fact is an important analgesic and anti-inflammatory drug, widely used for the treatment of postoperative pain, rheumatoid arthritis, and chronic pain. Consequently, diclofenac is often used in combination regimens and undesirable drug-drug interactions may occur.

Voltaren®, 50 mg soluble tablets, was selected among other possible diclofenac products because with this formulation peak concentration of diclofenamic acid is achieved at approximately 1 h, i.e. in less than 2 h.

The present interaction study was designed in agreement with the FDA Guideline on Drug Interaction studies, taking also in consideration the EMA guideline on the Investigation of drug interactions.

Eligibility criteria: Inclusion Criteria:

1. Signed written informed consent before inclusion in the study
2. Males and females, 25-55 years old
3. Body Mass Index (BMI): 18.5-30 kg/m2
4. Systolic blood pressure 100-139 mmHg, diastolic blood pressure 50-89 mmHg, heart rate 50-90 bpm
5. Ability to comprehend the full nature and purpose of the study
6. Females of child-bearing potential must use at least one of the following :

A non-hormonal intrauterine device or female condom with spermicide or contraceptive sponge with spermicide or diaphragm with spermicide or cervical cap with spermicide for at least 2 months before the screening visit A male sexual partner who agreed to use a male condom with spermicide A sterile sexual partner Female participants of non-child-bearing potential or in post-menopausal status for at least 1 year were admitted.

Exclusion Criteria:

1. Contraindications to MAO-B inhibitors, antiepileptic drugs, or to any NSAIDs
2. Clinically significant abnormalities in ECG
3. Clinically significant abnormal physical findings
4. Clinically significant abnormal laboratory values
5. Hypersensitivity or history of anaphylaxis to drugs or allergic reactions in general
6. Significant history of renal, hepatic, gastrointestinal, cardiovascular, respiratory, skin, haematological, endocrine or neurological diseases
7. Medications, including over the counter medications and herbal remedies, NSAID or anticoagulant use for 2 weeks before and during the entire study; morphine or other similar opioids, SSRIs, SNRIs, tri- or tetracyclic antidepressant, tramadol, pethidine, dextromethorphan, MAO inhibitors, meperidine derivatives and antiepileptic drugs, medicinal products that are BCRP substrates, any known enzyme inhibiting or inducing agent within 4 weeks preceding the screening visit.
8. Participation in the evaluation of any investigational product for 3 months before the study.
9. Blood donations for 3 months before the study
10. History of drug, alcohol, caffeine or tobacco abuse
11. Positive drug test at screening or day -1
12. Positive alcohol breath test at day -1
13. Abnormal diets or substantial changes in eating habits in the 4 weeks before the study; vegetarians
14. Positive or missing pregnancy test at screening or day -1, pregnant or lactating women

Primary outcomes:
measure: To Evaluate Plasma Diclofenamic Acid Extent of Exposure Reported as Plasma AUC After Single Administration of 50 mg Diclofenac Sodium, With and Without Co-administration of a Single 200 mg Dose of Safinamide.
timeFrame: 24 hours
Secondary outcomes:
measure: Evaluate Diclofenac Rate of Absorption Reported as Plasma Cmax After Single Administration of 50 mg Diclofenac With and Without 200 mg of Safinamide.
timeFrame: 24 hours
measure: Tmax and T1/2
timeFrame: 24 hours
measure: Lamda z
timeFrame: 24 hours
measure: Relative Bioavailability (Frel)
timeFrame: 24 hours
Other outcomes:
Locations:
city: Arzo
country: Switzerland
facility: Cross Research SA, Phase I Unit
state: Ticino
Study officials:
affiliation: Cross Research SA
name: Milko Radicioni, MD
role: PRINCIPAL_INVESTIGATOR
References: