A Phase I, Pharmacokinetics, Safety and Tolerability Study of Single and Multiple Oral Doses of Safinamide in Healthy Adult Chinese Volunteers
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 发起方
- Zambon SpA
- 入组人数
- 24
- 试验地点
- 1
- 主要终点
- Maximum Safinamide Plasma Concentration (Cmax)
研究概览
简要总结
This is a Phase I, single center, single and multiple-dose, open-label, randomised, parallel-group, pharmacokinetics, safety and tolerability study. The subjects will be randomised into two study cohorts to receive single and multiple doses of 50 mg safinamide (cohort 1), or single and multiple doses of 100 mg safinamide (cohort 2) as follows:
Cohort 1: One safinamide 50 mg film-coated tablet will be administered on day 1 followed by 7 safinamide 50 mg film-coated tablets in total from day 8 to day 14 and hence administered 1 tablet orally from day 8 to day 14.
Cohort 2: One safinamide 100 mg film-coated tablet will be administered on day 1 followed by 7 safinamide 100 mg film-coated tablets in total from day 8 to day 14 and hence administered 1 tablet orally from day 8 to day 14.
The investigational products will be administered in the morning, at 8:00±1hour, under fasting conditions, with 240 mL (total volume) of still mineral water. A mouth-and-hand check will be performed immediately after dosing to ensure treatment compliance.
The primary endpoint will assess the pharmacokinetic parameters after single and multiple dose administration of the study drug. The secondary endpoint will provide the safety and tolerability data after single and multiple dose administration of the study drug.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 45 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •Informed consent: signed written informed consent before inclusion in the study
- •Sex and Age: males and females, 18-45-year old inclusive
- •Ethnicity: Chinese
- •Weight: body weight ≥ 50 kg;
- •Body Mass Index: 19-26 kg/m2 inclusive
- •Vital signs: systolic blood pressure 100-139 mmHg, diastolic blood pressure 50-89 mmHg, heart rate 50-90 bpm, measured after 5 min at rest in the sitting/supine position
- •Full comprehension: ability to comprehend the full nature and purpose of the study, including possible risks and side effects; ability to co-operate with the investigator and to comply with the requirements of the entire study
- •No nicotine addiction (smoker subjects only): ability to abstain for smoking for the duration of the clinical study
- •Contraception and fertility (women only): women of child-bearing potential must be using at least one of the following reliable methods of contraception during the study and two weeks post-dose:
- •Hormonal oral, implantable, transdermal, or injectable contraceptives for at least 2 months before the screening visit
- •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 agrees to use a male condom with spermicide
- •A sterile sexual partner
- •Women of non-child-bearing potential or in post-menopausal status for at least 1 year will be admitted.
- •For all women, pregnancy test result must be negative at screening and day -1.
排除标准
- •Electrocardiogram (12-lead ECG in supine position): clinically significant abnormalities
- •Physical findings: clinically significant abnormal physical findings which could interfere with the objectives of the study
- •Laboratory analyses: clinically significant abnormal laboratory values indicative of physical illness
- •Allergy: ascertained or presumptive hypersensitivity to the active principle and/or formulations' ingredients; history of anaphylaxis to drugs or allergic reactions in general, which the investigator considers may affect the outcome of the study
- •Diseases: significant history of renal, hepatic, gastrointestinal, cardiovascular, respiratory, skin, haematological, endocrine or neurological diseases that may interfere with the aim of the study; positive result on HIV, hepatitis B (HBV) (except for vaccination), hepatitis C (HCV). Retinal degeneration, uveitis, inherited retinopathy or severe progressive diabetic retinopathy.
- •Medications: medications, including over the counter medications, herbal remedies and traditional Chinese remedies for 2 weeks before the start of the study. In particular statins and β-Hydroxy β-methylglutaryl-CoA (HMG-CoA)reductase inhibitors in the 2 weeks before the screening visit; medicinal products that are Breast Cancer Resistance Protein (BCRP) substrates; treatment with morphine or other similar opioids, whose concomitant use with Monoamine oxidase B (MAO-B) inhibitors is contraindicated, Selective serotonin reuptake inhibitors (SSRIs), Serotonin-norepinephrine reuptake inhibitors (SNRIs), tri- or tetracyclic antidepressant, tramadol, pethidine, dextromethorphan, Monoamino oxidase (MAO) inhibitors (e.g. selegiline), meperidine derivatives and antiepileptic drugs in the 4 weeks before the screening visit; treatment with any known enzyme inhibiting or inducing agent within 4 weeks preceding the screening visit. Hormonal contraceptives for women will be allowed
- •Investigative drug studies: participation in the evaluation of any investigational product for 3 months before this study
- •Blood donation: blood donations or blood components transfusion for 3 months before this study
- •Abuse drug, alcohol, caffeine, tobacco: history of drug, alcohol [>1 drink/day for females and >2 drinks/day for males, defined according to the USDA Dietary Guidelines 2015-2020], caffeine (>5 cups coffee/tea/day) or tobacco abuse (≥10 cigarettes or equivalent amount of tobacco per day within 3 months prior to day-1)
- •Abuse drug test: positive result at urine drug test at screening or day-1
- •Alcohol test: positive alcohol breath test at day -1
- •Diet: abnormal diets (<1600 or >3500 kcal/day) or substantial changes in eating habits in the 4 weeks before this study; vegetarians; consumption of grapefruit or products containing grapefruit within 48 hours prior to the enrolment; consumption of beverages containing xanthines (e.g. coffee, tea, soda, coffee, milk, energy drinks) within 48 hours prior to the enrolment
- •Pregnancy (females only): positive or missing pregnancy test at screening or day -1, pregnant or lactating women.
研究组 & 干预措施
Safinamide 50mg
The subjects will receive 50mg safinamide on Day 1 of Period 1 and on Days 8 to 14 in period 2.
干预措施: Safinamide 50 mg (Drug)
Safinamide 100mg
The subjects will receive 100mg safinamide on Day 1 of Period 1 and on Days 8 to 14 in period 2.
干预措施: Safinamide 100mg (Drug)
结局指标
主要结局
Maximum Safinamide Plasma Concentration (Cmax)
时间窗: Day 1 and Day 8
The Cmax was determined on Day 1 (after the first dose), on Day 8 (after the first multiple doses) of Safinamide.
Time Corresponding to Occurrence of Cmax (Tmax)
时间窗: Day 1 and Day 8
The tmax was determined on Day 1 (after the first dose), on Day 8 (after the first multiple dose) of Safinamide.
Area Under the Concentration-time Curve From Single-dose Administration to the Last Quantifiable Concentration-time t (AUC0-t)
时间窗: Day 1 and Day 8
The (AUC0-t) was determined on Day 1 (after the first dose), on Day 8 (after the first multiple doses) of Safinamide.
Area Under the Concentration-time Curve in the Tau Interval (From Single Dose Administration to 24 h Post Dose) (AUC0-24h)
时间窗: Day 1 and Day 8
The (AUC0-24h) was determined on Day 1 (after the first dose), on Day 8 (after the first multiple dose) of safinamide.
Last Quantifiable Concentration (Clast/Ct)
时间窗: Day 1
The (Clast/Ct) was determined on Day 1 (after the first dose) of safinamide.
Terminal Elimination Rate Constant (Kel)
时间窗: Day 1
Apparent terminal elimination rate constant, calculated, if feasible, from the slope of a log-linear regression using at least 3 last concentration \> lower limit of quantification (LLOQ) points. The Kel was determined on Day 1 (after the first dose) of safinamide.
Apparent Terminal Elimination Half Life (t1/2)
时间窗: Day 1
Apparent terminal elimination half-life, calculated, if feasible, as ln2/Kel. The t1/2 will be determined on Day 1 (after the first dose) of Safinamide.
Percentage of AUC(0-inf) Obtained by Extrapolation (%AUCex)
时间窗: Day 1
The %AUCex was determined on Day 1 (after the first dose) of Safinamide.
AUC From Time Zero Extrapolated to Infinity (AUC(0-inf))
时间窗: Day 1
Area under the concentration-time curve extrapolated to infinity, calculated, if feasible, as AUC0-t + Ct/Kel, where Ct is the last measurable drug concentration. The AUC(0-inf) was determined on day 1 (after the first dose) of Safinamide.
Apparent Volume of Distribution During Terminal Phase (Vd/F)
时间窗: Day 1
Apparent volume of distribution associated with the terminal slope, calculated, if feasible, as Dose/(AUC0-∞\*Kel). The Vd/F was determined on Day 1 (after the first dose) of safinamide.
Apparent Clearance Following Oral Administration (CL/F)
时间窗: Day 1
Apparent total body clearance, calculated, if feasible, as Dose/AUC0-∞. The CL/F was determined on Day 1 (after the first dose) of safinamide.
Mean Residence Time (MRT)
时间窗: Day 1
Mean residence time, calculated, if feasible, as AUMC0-∞/AUC0-∞, where AUMC0-∞ is area under the moment concentration-time curve extrapolated to infinity. The MRT was determined on Day 1 (after the first dose) of Safinamide.
Area Under the First Moment of the Concentration-time Curve (AUMC)
时间窗: Day 1
The AUMC was determined on Day 1 (after the first dose) of Safinamide.
Maximum Safinamide Plasma Concentration at Steady State (Cmax_ss)
时间窗: Day 14
The Cmax_ss was determined on day 14 (after the multiple-dose) of Safinamide.
Time Corresponding to Occurrence of Cmax_ss at Steady State (tmax_ss)
时间窗: Day 14
The tmax_ss was determined on day 14 (after the multiple-dose) of Safinamide.
Minimum Observed Concentration at Steady State (Cmin_ss)
时间窗: Day 14
The Cmin_ss was determined on day 14 (after the multiple dose) of Safinamide.
Area Under the Concentration-time Curve at Steady State From the Last Dose Administration to the Last Observed Concentration Time t (AUC0-t_ss)
时间窗: Day 14
The AUC0-t_ss was determined on Day 14 (after the multiple dose) of Safinamide.
AUC Over the Dosing Interval at Steady State (AUC0-τ_ss)
时间窗: Day 14
The AUC0-τ_ss was determined on Day 14 (after the multiple dose) of Safinamide.
Apparent Total Body Clearance at Steady-state, (CL/F_ss)
时间窗: Day 14
The CL/F_ss was determined on Day 14 (after the multiple dose) of Safinamide.
Average Safinamide Plasma Concentration at Steady State(Cave_ss)
时间窗: Day 14
Average safinamide plasma concentration at steady state, calculated as AUC0- 24h_ss /tau (24 h). The Cave_ss was determined on Day 14 (after the multiple dose) of Safinamide.
Accumulation Ratio, Based on AUC (Racc,AUC)
时间窗: Day 14
Racc,AUC was determined on Day 14 (after the multiple dose) of Safinamide.
Accumulation Ratio, Based on Cmax (Racc,Cmax)
时间窗: Day 14
Racc,Cmax was determined on Day 14 (after the multiple dose) of Safinamide.
Peak-trough Fluctuation Over One Dosing Interval at Steady-state (DF%)
时间窗: Day 14
Peak-trough fluctuation over one dosing interval at steady-state, calculated as (Cmax,ss - Cmin,ss)/Cave,ss\*100. The DF% was determined on Day 14 (after the multiple dose) of Safinamide.
Apparent Volume of Distribution at Steady-state Associated With the Terminal Slope (Vd/F_ss)
时间窗: Day 14
Apparent volume of distribution at steady-state associated with the terminal slope, calculated, if feasible, as Dose/( AUC0-24h_ss\*Kel). The Vd/F_ss was determined on Day 14 (after the multiple dose) of Safinamide.
次要结局
- Number of Subjects With Treatment Emergent Adverse Events (TEAEs)(Day 1 to18)