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

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.

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.

Study Overview

• Status: Completed
• Conditions: Anesthesia; Sedation
• Intervention / Treatment: Drug: HSK3486; Drug: rifampin , HSK3486

• Study Type: Interventional
• Enrollment (Actual): 16
• Phase: Phase 1

Contacts and Locations

Study Locations

• China
  • Shanghai, China
    • Shanghai Public Health Clinical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 45 years (Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Healthy males or females with full capacity for civil conduct, aged ≥18 and ≤45 years old. Both male and female subjects should be enrolled;
2. 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;
3. 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%;
4. 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);
5. 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;
6. 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:

1. 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;

2. In receipt of any one of the following medications or treatments during screening/baseline:

   1. 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;
   2. 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;
   3. In receipt of rifampin within 4 weeks prior to screening;
   4. 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);
   5. In receipt of propofol, other sedatives/anesthetics and/or opioid analgesics or compounds containing analgesics within 1 week prior to baseline;
   6. 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;

3. A history or evidence of any one of the following diseases prior to screening/baseline:

   1. 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);
   2. 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;
   3. History of GI tract diseases: Gastrointestinal obstruction, active GI bleed, potential for reflux and aspiration;

4. Laboratory results that meet any of the following during screening/baseline:

   1. Positive result for either HBsAg, HCV, HIV, or syphilis;

   2. Abnormal hepatic or renal function confirmed after re-examination;

      • ALT or AST > 1×ULN;
      • Creatinine > 1×ULN;
      • TBIL > 1.0×ULN;
5. 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;
6. Smoke more than 5 cigarettes per day and a total of more than 60 cigarettes within 3 months prior to screening;
7. Blood donation or blood loss ≥200 mL within 30 days prior to screening; plasma donation or plasma exchange within 7 days prior to screening;
8. 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;
9. Subjects expected to have surgery or hospitalization during the trial;
10. Subjects unsuitable for arterial blood collection, such as subjects who have positive Allen's test;
11. 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);
12. Subjects judged by the investigator to be unsuitable for participating in this trial for any reason.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: HSK3486; 0.4 mg/kg	Drug: HSK3486; Sequence 1: Intravenously infuse 0.4 mg/kg HSK3486 in the morning on an empty stomach. Complete infusion within 1 min.
Experimental: rifampin , HSK3486; 600 mg;0.4 mg/kg	Drug: rifampin , HSK3486; 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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

Collaborators and Investigators

• Sponsor: Sichuan Haisco Pharmaceutical Group Co., Ltd

Study record dates

Study Major Dates

• Study Start (Actual): December 14, 2018
• Primary Completion (Actual): January 31, 2019
• Study Completion (Actual): March 10, 2019

Study Registration Dates

• First Submitted: November 25, 2018
• First Submitted That Met QC Criteria: November 28, 2018
• First Posted (Actual): November 29, 2018

Study Record Updates

• Last Update Posted (Actual): August 20, 2019
• Last Update Submitted That Met QC Criteria: August 19, 2019
• Last Verified: November 1, 2018

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Anti-Bacterial Agents; Leprostatic Agents; Cytochrome P-450 Enzyme Inducers; Cytochrome P-450 CYP3A Inducers; Antitubercular Agents; Antibiotics, Antitubercular; Cytochrome P-450 CYP2B6 Inducers; Cytochrome P-450 CYP2C8 Inducers; Cytochrome P-450 CYP2C19 Inducers; Cytochrome P-450 CYP2C9 Inducers; Rifampin
• Other Study ID Numbers: HSK3486-103

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No