Healthy
Conditions
Keywords
PK study
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.
Interventions
DRUGDiclofenac sodium
Diclofenac sodium 50 mg single dose
DRUGDiclofenac sodium and safinamide
Diclofenac 50 mg single dose and safinamide 200 mg single dose
Sponsors
Cross Research S.A.
Zambon SpA
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
22 Years to 55 Years
Healthy volunteers
Yes
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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. | 24 hours | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Relative Bioavailability (Frel) | 24 hours | calculated as ratio between AUC0-t (test) / AUC0-t (reference) |
| Evaluate Diclofenac Rate of Absorption Reported as Plasma Cmax After Single Administration of 50 mg Diclofenac With and Without 200 mg of Safinamide. | 24 hours | 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. |
| Tmax and T1/2 | 24 hours | — |
| Lamda z | 24 hours | — |
Countries
Switzerland
Participant flow
Recruitment details
The recruitment started and finished on May 2015 and the study was performed in Switzerland at CROSS Research S.A., Phase I Unit, Via F.A. Giorgioli 14 CH-6864 Arzo, Switzerland
Pre-assignment details
Twenty-four (24) subjects were randomised in the study. One of the 24 subjects discontinued the study before study treatment. Twenty-two (22) subjects completed the study per protocol.
Participants by arm
| Arm | Count |
|---|---|
| Intervention Diclofenac sodium 50 mg oral tablets, single dose
Diclofenac sodium 50 mg oral tablets, single dose and safinamide 200 mg oral tablets, single dose | 23 |
| Total | 23 |
Baseline characteristics
| Characteristic | Intervention |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 23 Participants |
| Age, Continuous | 41.6 years STANDARD_DEVIATION 9.1 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 23 Participants |
| Region of Enrollment Switzerland | 23 participants |
| Sex: Female, Male Female | 12 Participants |
| Sex: Female, Male Male | 11 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 23 | 0 / 23 |
| serious Total, serious adverse events | 0 / 23 | 0 / 23 |
Outcome results
Primary
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.
Time frame: 24 hours
Population: healthy volunteers
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Diclofenac Sodium | 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. | 1323.28 h X ng per mL | Standard Deviation 390.53 |
| Diclofenac Sodium and Safinamide | 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. | 1381.32 h X ng per mL | Standard Deviation 393.77 |
Comparison: The PK parameters AUC0-t and Cmax 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.p-value: 0.190% CI: [80, 125]ANOVA
Secondary
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.
Time frame: 24 hours
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Diclofenac Sodium | Evaluate Diclofenac Rate of Absorption Reported as Plasma Cmax After Single Administration of 50 mg Diclofenac With and Without 200 mg of Safinamide. | 766.59 ng/mL | Standard Deviation 390.01 |
| Diclofenac Sodium and Safinamide | Evaluate Diclofenac Rate of Absorption Reported as Plasma Cmax After Single Administration of 50 mg Diclofenac With and Without 200 mg of Safinamide. | 833.50 ng/mL | Standard Deviation 443.34 |
90% CI: [96.4, 114.02]
Secondary
Lamda z
Time frame: 24 hours
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Diclofenac Sodium | Lamda z | 0.63 1/hours | Standard Deviation 0.22 |
| Diclofenac Sodium and Safinamide | Lamda z | 0.63 1/hours | Standard Deviation 0.16 |
Secondary
Relative Bioavailability (Frel)
calculated as ratio between AUC0-t (test) / AUC0-t (reference)
Time frame: 24 hours
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Diclofenac Sodium | Relative Bioavailability (Frel) | 107.67 ratio | Standard Deviation 28.84 |
| Diclofenac Sodium and Safinamide | Relative Bioavailability (Frel) | 109.61 ratio | Standard Deviation 32.14 |
Secondary
Tmax and T1/2
Time frame: 24 hours
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Diclofenac Sodium | Tmax and T1/2 | Tmax | 0.88 hours | Standard Deviation 0.41 |
| Diclofenac Sodium | Tmax and T1/2 | T1/2 | 1.24 hours | Standard Deviation 0.43 |
| Diclofenac Sodium and Safinamide | Tmax and T1/2 | Tmax | 1.0 hours | Standard Deviation 0.43 |
| Diclofenac Sodium and Safinamide | Tmax and T1/2 | T1/2 | 1.19 hours | Standard Deviation 0.4 |