A Study Evaluating Drug-Drug Interaction (DDI) Between HSK3486 Injectable Emulsion and Rifampin Capsules

Study Overview
=================
Brief Summary
-----------------
This is a Phase I, single-center, open-label, randomized,two-way crossover, propofol-controlled, two-stage study evaluating the safety and pharmacokinetics/pharmacodynamics of IV maintenance dose and IV single loade dose plus maintenance dose of HSK3486 emulsion for injection in healthy subjects.

Official Title
-----------------
A Single-Center, Open-Label, Randomized, Two-Stage, Two-Way Crossover Study Evaluating Drug-Drug Interaction (DDI) Between HSK3486 Injectable Emulsion and Rifampin Capsules in Healthy Subjects.

Conditions
-----------------
Anesthesia, Sedation

Intervention / Treatment
-----------------
* Drug: HSK3486
* Drug: rifampin , HSK3486


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Healthy males or females with full capacity for civil conduct, aged ≥18 and ≤45 years old. Both male and female subjects should be enrolled; Male subjects weighing ≥50 kg, female subjects weighing ≥45 kg. All subjects should have a body mass index (BMI) of ≥19.0 and ≤26.0 kg/m2; Blood pressure between 100-139/60-89 mmHg; heart rate between 60-99 beats/min; body temperature between 35.8-37.5 °C; respiratory rate between 12-20 breaths/min; SpO2 when inhaling ≥95%; Normal physical examinations, laboratory examinations (blood routine, blood biochemistry and urine routine), and 12-lead electrocardiogram (ECG), or abnormal but without clinical significance as judged by the investigators; no significantly potential difficult airway (modified Mallampati score I-II); No previous history of major organ primary diseases, such as liver, kidneys, digestive tract, blood, and metabolic diseases; no history of malignant hyperthermia and other genetic conditions; no history of mental/neurological diseases; no history of epilepsy; no contraindications for deep sedation/general anesthesia; no clinically significant history of anesthesia accidents; Subjects must understand the procedures and methods of this study, and be willing to provide informed consent and to complete the trial in strict accordance with trial protocol. Exclusion Criteria: Known sensitivity to excipients in HSK3486 injectable emulsion (soybean oil, glycerin, triglyceride, egg lecithin, sodium oleate and sodium hydroxide), rifampin, or contraindications mentioned in the prescribing information of rifampin; history of drug allergies (including anesthetics), allergic diseases, or those with hyperactive immune response; In receipt of any one of the following medications or treatments during screening/baseline: History of drug abuse or any signs of chronic benzodiazepines use (such as insomnia, anxiety, spasms) within 3 months prior to screening, or a positive urine drug test during baseline; Participated in clinical trials involving any medications or medical devices within 3 months prior to screening, or subjects who have participated in 3 or more drug clinical trials within the past year; In receipt of rifampin within 4 weeks prior to screening; Serious infection, trauma or major surgery within 4 weeks prior to screening; or acute disease with clinical significance (determined by the investigator) within 2 weeks prior to screening, including GI diseases or infections (such as respiratory or CNS infections); In receipt of propofol, other sedatives/anesthetics and/or opioid analgesics or compounds containing analgesics within 1 week prior to baseline; In receipt of prescription drugs, Chinese herbal medicines, over-the-counter drugs or food supplements (such as vitamins and calcium supplements) other than contraceptives, paracetamol, oral non-steroidal anti-inflammatory drugs, topical over-the-counter preparations, within 2 weeks prior to baseline; unless the principal investigator (PI) and the sponsor agree that the medication has no effect on the safety and PK/PD results of the trial; A history or evidence of any one of the following diseases prior to screening/baseline: History of cardiovascular diseases such as: postural hypotension, severe arrhythmia, heart failure, Adams-Stokes syndrome, unstable angina, myocardial infarction within 6 months before screening, tachycardia/bradycardia requiring medication, third-degree atrioventricular block or QTcF interval ≥450 ms (Fridericia's correction formula); Respiratory insufficiency, history of obstructive pulmonary disease, history of asthma, sleep apnea; history of failed tracheal intubation; history of bronchospasm requiring treatment within 3 months prior to screening; acute respiratory infection, and with obvious symptoms such as fever, wheezing, nasal congestion or cough within 1 week prior to baseline; History of GI tract diseases: Gastrointestinal obstruction, active GI bleed, potential for reflux and aspiration; Laboratory results that meet any of the following during screening/baseline: Positive result for either HBsAg, HCV, HIV, or syphilis; Abnormal hepatic or renal function confirmed after re-examination; ALT or AST > 1×ULN; Creatinine > 1×ULN; TBIL > 1.0×ULN; History of alcohol abuse within 3 months prior to screening, abuse defined as average of > 2 units of alcohol per day (1 unit = 360 mL beer or 45 mL liquor with 40% alcohol or 150 mL wine), or positive result for breath alcohol test during baseline; Smoke more than 5 cigarettes per day and a total of more than 60 cigarettes within 3 months prior to screening; Blood donation or blood loss ≥200 mL within 30 days prior to screening; plasma donation or plasma exchange within 7 days prior to screening; Subjects who consume any beverages or foods containing alcohol, grapefruit juice or methylxanthine (such as coffee, tea, coca-cola, chocolate, functional drinks), to participate in strenuous physical activities and other factors that may affect drug absorption, distribution, metabolism, and excretion within 2 days prior to enrollment; subjects who are unable to fast for 8 hours prior to dose administration; Subjects expected to have surgery or hospitalization during the trial; Subjects unsuitable for arterial blood collection, such as subjects who have positive Allen's test; Women who are pregnant or breastfeeding; women of child-bearing potential or men who are unwilling to use contraception during the trial; subjects who are planning pregnancy within 1 month after the completion of the trial (including male subjects); Subjects judged by the investigator to be unsuitable for participating in this trial for any reason.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 45 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: HSK3486<br>0.4 mg/kg | Drug: HSK3486<br>* Sequence 1: Intravenously infuse 0.4 mg/kg HSK3486 in the morning on an empty stomach. Complete infusion within 1 min.<br>|
| Experimental: rifampin , HSK3486<br>600 mg;0.4 mg/kg | Drug: rifampin , HSK3486<br>* Sequence 2: Orally take 600 mg rifampin once a day for 8 consecutive days in the morning on an empty stomach, followed by 1 min intravenous infusion of 0.4 mg/kg HSK3486 30 min later.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Peak concentration (Cmax) |  | From the start of HSK3486 administration to 24 h after the start of administration on day 1 | 
| Area under the concentration-time curve (AUC0-t, AUC0-∞) |  | From the start of HSK3486 administration to 24 h after the start of administration on day 1 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Terminal elimination half life (t1/2) |  | From the start of HSK3486 administration to 24 h after the start of administration on day 1 | 
| Time to fully awake |  | From the start of HSK3486 administration until the subjects is fully awake on day 1 | 
| MOAA/S(modified observer's assessment of alert /sedation)-time curve | Observe the change of modified observer's assessment of alert /sedation during the whole trial | From the start of HSK3486 administration until the subjects is fully awake on day 1 | 
| BIS(bispectral index)-time curve | Observe the changes of bispectral index during the whole trial | From the start of HSK3486 administration to 60 min after the start of administration on day 1 | 
| Blood pressure | Observe the changes of blood pressure during the whole trial | From the start of HSK3486 administration to 24 h after the start of administration on day 1 | 
| Heart rate | Observe the changes of heart rate during the whole trial | From the start of HSK3486 administration to 24 h after the start of administration on day 1 | 
| Respiratory rate or blood oxygen saturation | Observe the changes of respiratory rate or blood oxygen saturation during the whole trial | From the start of HSK3486 administration to 24 h after the start of administration on day 1 | 
| Blood routine test | Observe the changes of blood routine test during the whole trial | From the start of HSK3486 administration to 24 h after the start of administration on day 1 | 
| Urine routine test | Observe the changes of urine routine test during the whole trial | From the start of HSK3486 administration to 24 h after the start of administration on day 1 | 
| Blood biochemical examination | Observe the changes of Blood biochemical examination during the whole trial | From the start of HSK3486 administration to 24 h after the start of administration on day 1 | 
| 12-Electrocardiogram | Observe the changes of heart rate, RR interval, QT interval , QTcF interval , PR interval and QRS interval of electrocardiogram during the whole trial | From the start of HSK3486 administration to 24 h after the start of administration on day 1 | 
| Number of patients with adverse events | Safety endpoits | From the start of HSK3486 administration to 24 h after the start of administration on day 1 | 
| Concurrent medications | Safety endpoits | From the start of HSK3486 administration to 24 h after the start of administration on day 1 |