A Study to Investigate the Drug-drug Interactions (DDIs) Between SKLB1028 and Midazolam in Healthy Subjects

A Single-center, Open-label, Phase I Drug-drug Interaction Clinical Study to Investigate the Effect of SKLB1028 on the Pharmacokinetics of Midazolam in Healthy Subjects

This is a single-center, open-label phase I clinical study to investigate the effect of SKLB1028 on the pharmacokinetics of Midazolam and its metabolite 1'-OH-midazolam in healthy subjects. This study also aims to evaluate the safety and tolerability of SKLB1028 in the presence of Midazolam.

Study Overview

• Status: Completed
• Conditions: Healthy Subjects
• Intervention / Treatment: Drug: SKLB1028; Drug: Midazolam

Detailed Description

This study aims to characterize the drug-drug Interactions (DDI) potential of SKLB1028 with the sensitive index substrate drug (Midazolam) in Healthy Subjects. The study consists of a screening period (Day -14 to Day -2), a baseline period (Day -1), a treatment period, and a follow-up visit period.

• Study Type: Interventional
• Enrollment (Actual): 14
• Phase: Phase 1

Contacts and Locations

Study Locations

• China
  • Beijing, China
    • Beijing Friendship Hospital, Capital Medical University

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

-

Healthy subjects:

1. Voluntarily sign the informed consent form, understand the trial procedures, and be willing to comply with all trial procedures and restrictions;
2. 18 ≤ age ≤45, male;
3. Subjects with weight ≥50.0 kg and body mass index (BMI) 19-26 kg/m^2 (inclusive);
4. Subjects are willing to use effective non-hormonal contraceptives such as sexual abstinence, and not allowed to donate sperm from screening to the 6 months after the last dose administration unless permanent contraception has been taken, such as vasectomy;
5. Ability to communicate well with researchers, and be willing to comply with all trial requirements.

Exclusion Criteria:

1. Allergic constitution, including a history of allergy to any of the study drugs or other similarly structured drugs;
2. Previous or current severe diseases, such as cardiovascular, respiratory, gastrointestinal, endocrine, hematological, psychiatric/neurological systems diseases, or any other disease that can interfere with the results of the study;
3. Subjects with sleep apnea syndrome;
4. Subjects with rare hereditary problems of galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption;
5. Subjects with acute angle closure glaucoma;
6. Subjects who have previously undergone surgery that may affect the absorption, distribution, metabolism, or excretion of the drug (e.g., subtotal gastrectomy), or who have a scheduled surgical plan during the study period;
7. Use of any inhibitors or inducers of CYP3A4, or any strong inhibitors or inducers of CYP2C8 or P-gp within 2 weeks prior to screening;
8. Use of any prescription drug, over-the-counter drug, herbal medicine or health products within 2 weeks prior to screening;
9. History of drug abuse within 1 year prior to screening, or positive urine drug screen at screening;
10. Smoking more than 5 cigarettes per day within 6 months prior to screening;
11. Average daily intake of alcohol more than 14 units (14 units ≈285 mL of beer, or 25 mL of liquor, or 150 mL of wine) within 4 weeks prior to screening, or a positive ethanol breath test at screening;
12. Consumption of grapefruit juice, methylxanthine-rich food or beverage (such as coffee, tea, cola, chocolate, energy drinks) within 48 h before the administration, or those who have had strenuous exercise, or have other factors affecting absorption, distribution, metabolism, excretion, etc of the drug;
13. Subjects who have received vaccinations within 4 weeks prior to screening;
14. Participation in another clinical trial within 3 months before screening (whichever is administrated);
15. Blood donation (or blood loss) ≥200 mL within 4 weeks prior to the screening, or who have a blood donation plan during the entire study or within 1 months after the study;
16. Any abnormalities of clinical significance in physical examination, vital signs, clinical laboratory tests (routine blood test, blood biochemistry, routine urine test, coagulation function), anteroposterior chest radiograph or chest CT scan;
17. Abnormalities of clinical significance in 12-lead ECG examination (such as tachycardia/bradycardia in need of medical treatment, II-III degree atrioventricular block, QTcF>450 ms or any other clinically significant abnormalities);
18. Any positive test result of hepatitis B surface antigen or hepatitis C virus antibody, or subjects with a history of hepatitis B;
19. Any positive test result of anti-human immunodeficiency virus antibody or anti-Treponema pallidum specific antibody;
20. Subjects with a history of fainting needle or blood, cannot tolerate vein puncture for blood collection;
21. Any condition that, in the opinion of the Investigator, may prevent the subject from completing the study or pose a significant risk to the subject.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: The DDI of SKLB1028 and Midazolam; Eligible subjects received a single dose of Midazolam 15 mg on Day 1, and took a single dose of Midazolam 15 mg and a single dose of SKLB1028 150 mg with dosing interval of 0.5 h on Day 3.	Drug: SKLB1028; SKLB1028, capsule, oral; Drug: Midazolam; Midazolam Maleate, tablet, oral

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Maximum concentration (Cmax)of Midazolam and its metabolite 1'-OH-midazolam	Day 1 and Day 3(0, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24 hrs post-dose)
Area under the concentration-time curve (AUC) from 0 to the last measurable concentration (AUC0-t) of Midazolam and its metabolite 1'-OH-midazolam	Day 1 and Day 3(0, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24 hrs post-dose)
AUC extrapolated to infinity (AUCinf) of Midazolam and its metabolite 1'-OH-midazolam	Day 1 and Day 3(0, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24 hrs post-dose)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to Cmax (Tmax) of Midazolam and its metabolite 1'-OH-midazolam		Day 1 and Day 3(0, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24 hrs post-dose)
Terminal elimination half-life (t1/2) of Midazolam and its metabolite 1'-OH-midazolam		Day 1 and Day 3(0, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24 hrs post-dose)
Apparent Clearance (CLz/F) of Midazolam		Day 1 and Day 3(0, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24 hrs post-dose)
Apparent volume of distribution (Vz/F) of Midazolam		Day 1 and Day 3(0, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24 hrs post-dose)
Number of participants with treatment-related adverse events as assessed by CTCAE v5.0		Throughout the study period, with an average of 10 days
Clinically significant changes from baseline in routine blood test were recorded as AEs at each visit time point.	Routine blood test included cell count (white blood cells, platelets, basophils, eosinophils, neutrophils, lymphocytes and monocytes) in 10^9/L.	Throughout the study period, with an average of 10 days
Clinically significant changes from baseline in routine blood test were recorded as AEs at each visit time point.	Routine blood test included red blood cell count in 10^12/L.	Throughout the study period, with an average of 10 days
Clinically significant changes from baseline in routine blood test were recorded as AEs at each visit time point.	Routine blood test included hemoglobin in g/L.	Throughout the study period, with an average of 10 days
Clinically significant changes from baseline in blood biochemistry test were recorded as AEs at each visit time point.	Blood biochemistry test included total bilirubin and serum creatinine in μmol/L.	Throughout the study period, with an average of 10 days
Clinically significant changes from baseline in blood biochemistry test were recorded as AEs at each visit time point.	Blood biochemistry test included alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase and creatine kinase in U/L.	Throughout the study period, with an average of 10 days
Clinically significant changes from baseline in blood biochemistry test were recorded as AEs at each visit time point.	Blood biochemistry test included total protein and albumin in g/L.	Throughout the study period, with an average of 10 days
Clinically significant changes from baseline in blood biochemistry test were recorded as AEs at each visit time point.	Blood biochemistry test included total cholesterol, triglyceride and blood glucose in mmol/L.	Throughout the study period, with an average of 10 days
Clinically significant changes from baseline in routine urine test were recorded as AEs at each visit time point.	Routine urine test included urobilinogen, protein, glucose and ketones (positive or negative).	Throughout the study period, with an average of 10 days
Clinically significant changes from baseline in routine urine test were recorded as AEs at each visit time point.	Routine urine test included pH value and specific gravity.	Throughout the study period, with an average of 10 days
Clinically significant changes from baseline in coagulation function test were recorded as AEs at each visit time point.	Coagulation function test included prothrombin time and activated partial thromboplastin time in seconds.	Throughout the study period, with an average of 10 days
Clinically significant changes from baseline in coagulation function test were recorded as AEs at each visit time point.	Coagulation function test included antithrombin III as percentage.	Throughout the study period, with an average of 10 days
Clinically significant changes from baseline in coagulation function test were recorded as AEs at each visit time point.	Coagulation function test included fibrinogen in g/L.	Throughout the study period, with an average of 10 days
Clinically significant changes from baseline in 12-lead electrocardiogram (ECG) examination were recorded as AEs at each visit time point.	ECG monitoring included heart rate in bpm.	Throughout the study period, with an average of 10 days
Clinically significant changes from baseline in 12-lead electrocardiogram (ECG) examination were recorded as AEs at each visit time point.	ECG monitoring included P-R, QRS, QT and QTcF in ms.	Throughout the study period, with an average of 10 days
Clinically significant changes from baseline in vital signs examination were recorded as AEs at each visit time point.	Vital signs monitoring included body temperature in degrees Celsius.	Throughout the study period, with an average of 10 days
Clinically significant changes from baseline in vital signs examination were recorded as AEs at each visit time point.	Vital signs monitoring included respiratory rate and pulse in times per minute.	Throughout the study period, with an average of 10 days
Clinically significant changes from baseline in vital signs examination were recorded as AEs at each visit time point.	Vital signs monitoring included systolic blood pressure and diastolic blood pressure in mmHg.	Throughout the study period, with an average of 10 days
Clinically significant changes from baseline in physical examination were recorded as AEs at each visit time point.	Physical examination included general conditions, skin, mucous membranes, head, neck, chest, abdomen, spine, limbs, nervous system, and lymphatic system.	Throughout the study period, with an average of 10 days

Collaborators and Investigators

• Sponsor: CSPC ZhongQi Pharmaceutical Technology Co., Ltd.

Study record dates

Study Major Dates

• Study Start (ACTUAL): June 7, 2021
• Primary Completion (ACTUAL): July 9, 2021
• Study Completion (ACTUAL): July 9, 2021

Study Registration Dates

• First Submitted: September 15, 2021
• First Submitted That Met QC Criteria: September 26, 2021
• First Posted (ACTUAL): October 7, 2021

Study Record Updates

• Last Update Posted (ACTUAL): October 7, 2021
• Last Update Submitted That Met QC Criteria: September 26, 2021
• Last Verified: September 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Anesthetics, Intravenous; Anesthetics, General; Anesthetics; Tranquilizing Agents; Psychotropic Drugs; Hypnotics and Sedatives; Adjuvants, Anesthesia; Anti-Anxiety Agents; GABA Modulators; GABA Agents; Midazolam
• Other Study ID Numbers: HA114-CSP-011

Drug and device information, study documents

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