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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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

Conditions
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Healthy Subjects

Intervention / Treatment
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* Drug: SKLB1028
* Drug: Midazolam


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: - Healthy subjects: Voluntarily sign the informed consent form, understand the trial procedures, and be willing to comply with all trial procedures and restrictions; 18 ≤ age ≤45, male; Subjects with weight ≥50.0 kg and body mass index (BMI) 19-26 kg/m^2 (inclusive); 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; Ability to communicate well with researchers, and be willing to comply with all trial requirements. Exclusion Criteria: Allergic constitution, including a history of allergy to any of the study drugs or other similarly structured drugs; 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; Subjects with sleep apnea syndrome; Subjects with rare hereditary problems of galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption; Subjects with acute angle closure glaucoma; 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; 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; Use of any prescription drug, over-the-counter drug, herbal medicine or health products within 2 weeks prior to screening; History of drug abuse within 1 year prior to screening, or positive urine drug screen at screening; Smoking more than 5 cigarettes per day within 6 months prior to screening; 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; 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; Subjects who have received vaccinations within 4 weeks prior to screening; Participation in another clinical trial within 3 months before screening (whichever is administrated); 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; 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; 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); Any positive test result of hepatitis B surface antigen or hepatitis C virus antibody, or subjects with a history of hepatitis B; Any positive test result of anti-human immunodeficiency virus antibody or anti-Treponema pallidum specific antibody; Subjects with a history of fainting needle or blood, cannot tolerate vein puncture for blood collection; 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.

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

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: The DDI of SKLB1028 and Midazolam<br>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<br>* SKLB1028, capsule, oral<br>Drug: Midazolam<br>* Midazolam Maleate, tablet, oral<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | 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 |