Drug Interaction Study of Safinamide and a BCRP Substrate, Diclofenac, Concomitantly Administered to Healthy Volunteers

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.

Study Overview

• Status: Completed
• Conditions: Healthy
• Intervention / Treatment: Drug: Diclofenac sodium; Drug: Diclofenac sodium and safinamide

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.

• Study Type: Interventional
• Enrollment (Actual): 24
• Phase: Phase 1

Contacts and Locations

Study Locations

• Switzerland
  • Ticino
    • Arzo, Ticino, Switzerland, 6864
      • Cross Research SA, Phase I Unit

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 22 years to 55 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Diclofenac sodium; Diclofenac sodium 50 mg oral tablets, single dose	Drug: Diclofenac sodium; Diclofenac sodium 50 mg single dose; Other Names: Voltaren
Active Comparator: Diclofenac sodium and safinamide; Diclofenac sodium 50 mg oral tablets, single dose, and safinamide 200 mg oral tablets, single dose	Drug: Diclofenac sodium and safinamide; Diclofenac 50 mg single dose and safinamide 200 mg single dose; Other Names: Voltaren and Xadago

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Plasma diclofenamic acid AUC0-t after T2 single dose, with and without T1 co-administration. To measure AUC plasma samples were taken by the participants at different time points, and the concentrations of diclofenac and safinamide were measured. AUC0-t is the area under the concentration-time curve from administration to the last observed concentration time t; PK parameters AUC0-t were analysed using analysis of variance (ANOVA). Before analysis, the data were transformed using a neperian logarithmic transformation. ANOVA was performed taking into account treatment, period, sequence and subject (sequence) as fixed effects with a variance components structure of the covariance matrix.	24 hours

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Evaluate Diclofenac Rate of Absorption Reported as Plasma Cmax After Single Administration of 50 mg Diclofenac With and Without 200 mg of Safinamide.	Cmax, of plasma diclofenamic acid after T2 single dose, with and without T1 co-administration. The parametric point estimators (PE) for the ratios of T2 treatment with T1 co-administration / T2 treatment without T1 co-administration for the PK parameters under consideration, and the two-sided 90% confidence interval (CI), were calculated using the adjusted least squares means (LSMEANS) from the ANOVA. LSmeans differences obtained in the log scale for Cmax were back-transformed to obtain the PE (i.e. geometric mean ratio) and the two-sided 90% CI as percentages.	24 hours
Tmax and T1/2		24 hours
Lamda z		24 hours
Relative Bioavailability (Frel)	calculated as ratio between AUC0-t (test) / AUC0-t (reference)	24 hours

Collaborators and Investigators

• Sponsor: Zambon SpA
• Collaborators: Cross Research S.A.
• Investigators: Principal Investigator: Milko Radicioni, MD, CROSS Research SA

Study record dates

Study Major Dates

• Study Start: May 1, 2015
• Primary Completion (Actual): May 1, 2015
• Study Completion (Actual): May 1, 2015

Study Registration Dates

• First Submitted: July 3, 2015
• First Submitted That Met QC Criteria: July 8, 2015
• First Posted (Estimate): July 13, 2015

Study Record Updates

• Last Update Posted (Estimate): April 15, 2016
• Last Update Submitted That Met QC Criteria: April 14, 2016
• Last Verified: April 1, 2016

More Information

Terms related to this study

• Keywords: PK study
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Peripheral Nervous System Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Cyclooxygenase Inhibitors; Diclofenac
• Other Study ID Numbers: Z7219J01

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No
• IPD Plan Description: Bioequivalence data are to be considered as a whole in all subjects (90%CI).