Drug-Drug Interaction Study of Itraconazole, Rifampicin and Midazolam With SIM0417/Ritonavir in Healthy Participants

An Open Labe Study to Evaluate the Drug-Drug Interaction of Itraconazole, Rifampicin and Midazolam With SIM0417/Ritonavir in Healthy Adult Chinese Participants

This is a phase 1, open-label, fixed-sequence, 2-period drug-drug interaction study to evaluate the pharmacokinetic interactions of itraconazole, rifampicin, midazolam, and SIM0417/ritonavir in healthy Chinese subjects.

Study Overview

• Status: Completed
• Conditions: Healthy Volunteers
• Intervention / Treatment: Drug: Cohort 1: SIM0417/ritonavir and itraconazole; Drug: Cohort 2: SIM0417/ritonavir and rifampicin; Drug: Cohort 3: SIM0417/ritonavir and midazolam

Detailed Description

This is a phase 1, open-label, fixed-sequence, 2-period drug-drug interaction study which was divided into three cohorts.

Cohort 1: to evaluate the effect of the CYP3A4 inhibitor itraconazole on the pharmacokinetics of SIM0417 and ritonavir in healthy participants.

Cohort 2: to evaluate the effect of the CYP3A4 inducer rifampicin on the pharmacokinetics of SIM0417 and ritonavir in healthy participants.

Cohort 3: to evaluate the effect of SIM0417/ ritonavir on the pharmacokinetics of CYP3A4 substrate midazolam in healthy participants.

• Study Type: Interventional
• Enrollment (Actual): 36
• Phase: Phase 1

Contacts and Locations

Study Locations

• China
  • Shandong
    • Jinan, Shandong, China, 250014
      • Shandong First Medical University

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. Fully understand the research content, process, and potential risks of this trial, voluntarily participate in the clinical trial and sign the informed consent,
2. Healthy male and female subjects aged ≥18 years and ≤45 years old.
3. Male weight ≥50kg, female weight ≥45kg, body mass index ≥19 kg/m2 and ≤28 kg/m2.
4. Subjects agree to use generally accepted effective contraception from the time they sign the informed consent form. And female subjects of Cohort 1 agree to take recognized effective contraceptive measures during the study period and for the next menstrual cycle after the last dose of the study drug (male subjects up to 1 month after the last dose of the study drug ). Subjects of cohort 2 agree to take recognized effective contraceptive measures during the study period and within 1 month after the last dose of the study drug. Subjects of cohort 3 agree to take recognized effective contraceptive measures during the study period and within 3 months after the last dose of the study drug. Female subjects had been using effective contraception for 14 days prior to screening.

Exclusion Criteria:

1. Any diseases that may affect the study results or the safety and status of the subjects, including but not limited to the central nervous system, respiratory system, cardiovascular system, alimentary system, blood and lymphatic system, endocrine system, musculoskeletal system, hepatic and kidney function obstacle.
2. Difficulty in venous blood collection, a history of fainting blood or needles, or those who cannot tolerate blood collection with intravenous indwelling needles.
3. With dysphagia or any history of gastrointestinal diseases that affect drug absorption.
4. Have special requirements for diet and cannot comply with the diet provided and corresponding regulations.
5. With specific allergic history ( asthma, urticaria, eczema, etc. ) or allergic constitution ( such as those allergic to two or more drugs, food such as milk, and pollen ) or allergic to any component of the research drug or research drug.
6. With special diet ( including pitaya, mango, grapefruit, food or beverage containing caffeine, etc. ) or intense exercise taken within 48 h before the first administration of the drug.
7. Taken of any prescription, non-prescription, vitamin, or herbal medicine within 4 weeks before and during the screening period and/or any vitamin, health care products were taken within 2 weeks before and during the screening period.
8. During the first 3 months prior to screening or from the screening period to the first administration period, alcohol was often consumed, i.e., more than 2 units of alcohol per day ( 1 unit = 360 mL beer or 45 mL spirits with 40 % alcohol or 150 mL wine ); or alcohol breath test positive.
9. More than 5 cigarettes per day during the 3 months prior to screening.
10. Participated in any drug clinical trial as a subject within 3 months prior to screening and took the study drug.
11. With blood donation or blood loss greater than 200 mL within 3 months prior to screening, or blood transfusion or blood products were received within 4 weeks.
12. Have a history of drug abuse or a positive drug abuse screen.
13. At the time of screening or baseline, the blood pressure in the resting state and the pulse are within the following ranges: such as systolic blood pressure <90 mmHg or ≥140 mmHg, diastolic blood pressure <60 mmHg or ≥90 mmHg, pulse <55 bpm or >100 bpm.
14. Electrocardiographic QTc > 450 msec (Fridericia formula) at screening and/or baseline, or presence of risk factors for Torsade de Pointes (eg, history of heart failure, history of hypokalemia, family with prolonged QT syndrome) history), or other abnormal clinical significance (judged by the investigator).
15. HBV surface antigen, HCV antibody, HIV, or syphilis are positive during screening.
16. Physical examination, vital signs, ECG, blood routine, blood biochemistry ( serum creatinine, total bilirubin> 1.0 × ULN, ALT, AST, triglyceride>1.1 ULN)), coagulation function, thyroid function, urine routine, chest X-ray, abdominal B-scan ultrasonography results were abnormal and have clinical significance (judged by the investigator).
17. Those who have been vaccinated within 1 month before screening, or have been vaccinated with a COVID-19 vaccine within 1 week before screening, or plan to be vaccinated during the treatment or within 2 weeks after the last dose of study drug.
18. Be positive in SARS-CoV-2 nucleic acid test at screening.
19. Those who had undergone major surgery within 6 months prior to screening or were scheduled to undergo surgery during the study period and were determined by the investigators to be unsuitable for inclusion.
20. Subjects have acute disease with clinical significance that judged unsuitable for inclusion judged by the investigator within 1 month before screening.
21. Females who are pregnant or breastfeeding or positive result from pregnancy test.
22. Subjects have other conditions that are not suitable for participating in this research, or the subjects may not be able to complete this research for other reasons (judged by the investigator).

Study Plan

How is the study designed?

Design Details

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

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Cohort 1: SIM0417/ritonavir and itraconazole; Interaction between SIM0417/ritonavir and itraconazole	Drug: Cohort 1: SIM0417/ritonavir and itraconazole; SIM0417/Ritonavir: Dose: 750 mg SIM0417 coadministered with 100 mg ritonavir once: Day1-Day2, Day9-Day10, BID; Day3,Day11(once only in the morning); Itraconazole：Dose: 200mg once；Day6-Day13, QD; Other Names: Interaction between SIM0417/ritonavir and itraconazole
Experimental: Cohort 2: SIM0417/ritonavir and rifampicin; Interaction between SIM0417/ritonavir and rifampicin	Drug: Cohort 2: SIM0417/ritonavir and rifampicin; SIM0417/Ritonavir:Dose: 750 mg SIM0417 coadministered with 100 mg ritonavir once: Day1,Day11(once only in the morning); Rifampicin：Dose: 0.6g once; Day4-Day12, QD; Other Names: Interaction between SIM0417/ritonavir and rifampicin
Experimental: Cohort 3: SIM0417/ritonavir and midazolam; Interaction between SIM0417/ritonavir and midazolam	Drug: Cohort 3: SIM0417/ritonavir and midazolam; SIM0417/Ritonavir: 750 mg SIM0417 coadministered with 100 mg ritonavir, Day3-Day6, BID; Day7(once only in the morning) Midazolam：Dose: 2mg once; Day1, Day6, QD; Other Names: Interaction between SIM0417/ritonavir and midazolam

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cmax of SIM0417 in cohort 1	Cmax of SIM0417 when SIM0417/ritonavir is multiple administered or combined with itraconazole	Up to Day 14
Ctrough of SIM0417 in cohort 1	Ctrough of SIM0417 when SIM0417/ritonavir is multiple administered or combined with itraconazole	Up to Day 14
AUC0-t of SIM0417 in cohort 1	AUC0-t of SIM0417 when SIM0417/ritonavir is multiple administered or combined with itraconazole	Up to Day 14
AUC0-∞ of SIM0417 in cohort 1	AUC0-∞ of SIM0417 when SIM0417/ritonavir is multiple administered or combined with itraconazole	Up to Day 14
AUCtau of SIM0417 in cohort 1	AUCtau of SIM0417 when SIM0417/ritonavir is multiple administered or combined with itraconazole	Up to Day 14
t1/2 of SIM0417 in cohort 1	t1/2 of SIM0417 when SIM0417/ritonavir is multiple administered or combined with itraconazole	Up to Day 14
Cmax of SIM0417 in cohort 2	Cmax of SIM0417 when SIM0417/ritonavir is single dosed administration or combined with rifampicin	Up to Day 14
AUC0-t of SIM0417 in cohort 2	AUC0-t of SIM0417 when SIM0417/ritonavir is single dosed administration or combined with rifampicin	Up to Day 14
AUC0-∞ of SIM0417 in cohort 2	AUC0-∞ of SIM0417 when SIM0417/ritonavir is single dosed administration or combined with rifampicin	Up to Day 14
t1/2 of SIM0417 in cohort 2	t1/2 of SIM0417 when SIM0417/ritonavir is single dosed administration or combined with rifampicin	Up to Day 14
Cmax of midazolam	Cmax of midazolam when midazolam is single dosed administration or combined with SIM0417/ritonavir	Up to Day 9
AUC0-t of midazolam	AUC0-t of midazolam when midazolam is single dosed administration or combined with SIM0417/ritonavir	Up to Day 9
AUC0-∞ of midazolam	AUC0-∞ of midazolam when midazolam is single dosed administration or combined with SIM0417/ritonavir	Up to Day 9
t1/2 of midazolam	t1/2 of midazolam when midazolam is single dosed administration or combined with SIM0417/ritonavir	Up to Day 9

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Adverse Events of Cohort 1	Number of Participants With Adverse Events	Up to Day 26
Adverse Events of Cohort 2	Number of Participants With Adverse Events	Up to Day 25
Adverse Events of Cohort 3	Number of Participants With Adverse Events	Up to Day 20
Vital Signs	Number of Participants With Clinically Notable Vital Signs	Up to Day 14
ECG	Number of Participants With Clinically Notable Electrocardiogram (ECG) Values	Up to Day 14
Laboratory Tests	Number of Participants With Clinically Notable Laboratory Tests	Up to Day 14
Cmax of ritonavir in Cohort 1	Cmax of ritonavir when SIM0417/ritonavir is multiple administered or combined with itraconazole	Up to Day 14
Ctrough of ritonavir in Cohort 1	Ctrough of ritonavir when SIM0417/ritonavir is multiple administered or combined with itraconazole	Up to Day 14
AUC0-t of ritonavir in Cohort 1	AUC0-t of ritonavir when SIM0417/ritonavir is multiple administered or combined with itraconazole	Up to Day 14
AUC0-∞ of ritonavir in Cohort 1	AUC0-∞ of ritonavir when SIM0417/ritonavir is multiple administered or combined with itraconazole	Up to Day 14
AUCtau of ritonavir in Cohort 1	AUCtau of ritonavir when SIM0417/ritonavir is multiple administered or combined with itraconazole	Up to Day 14
t1/2 of ritonavir in Cohort 1	t1/2 of ritonavir when SIM0417/ritonavir is multiple administered or combined with itraconazole	Up to Day 14
Cmax of ritonavir in Cohort 2	Cmax of ritonavir when SIM0417/ritonavir is single dosed administration or combined with rifampicin	Up to Day 14
AUC0-t of ritonavir in Cohort 2	AUC0-t of ritonavir when SIM0417/ritonavir is single dosed administration or combined with rifampicin	Up to Day 14
AUC0-∞ of ritonavir in Cohort 2	AUC0-∞ of ritonavir when SIM0417/ritonavir is single dosed administration or combined with rifampicin	Up to Day 14
t1/2 of ritonavir in Cohort 2	t1/2 of ritonavir when SIM0417/ritonavir is single dosed administration or combined with rifampicin	Up to Day 14

Collaborators and Investigators

• Sponsor: Jiangsu Simcere Pharmaceutical Co., Ltd.

Study record dates

Study Major Dates

• Study Start (Actual): December 29, 2022
• Primary Completion (Actual): January 26, 2023
• Study Completion (Actual): February 14, 2023

Study Registration Dates

• First Submitted: December 19, 2022
• First Submitted That Met QC Criteria: December 19, 2022
• First Posted (Actual): December 27, 2022

Study Record Updates

• Last Update Posted (Estimate): February 21, 2023
• Last Update Submitted That Met QC Criteria: February 19, 2023
• Last Verified: January 1, 2023

More Information

Terms related to this study

• Keywords: Drug-drug interaction
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Central Nervous System Depressants; Antiviral Agents; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Anti-HIV Agents; Anti-Retroviral Agents; Anesthetics, Intravenous; Anesthetics, General; Anesthetics; Hormones, Hormone Substitutes, and Hormone Antagonists; Protease Inhibitors; Anti-Bacterial Agents; Tranquilizing Agents; Psychotropic Drugs; Hypnotics and Sedatives; Adjuvants, Anesthesia; Anti-Anxiety Agents; GABA Modulators; GABA Agents; Cytochrome P-450 CYP3A Inhibitors; Cytochrome P-450 Enzyme Inhibitors; Leprostatic Agents; Hormone Antagonists; Cytochrome P-450 Enzyme Inducers; Antifungal Agents; Steroid Synthesis Inhibitors; Cytochrome P-450 CYP3A Inducers; HIV Protease Inhibitors; Viral Protease Inhibitors; Antitubercular Agents; 14-alpha Demethylase Inhibitors; Antibiotics, Antitubercular; Cytochrome P-450 CYP2B6 Inducers; Cytochrome P-450 CYP2C8 Inducers; Cytochrome P-450 CYP2C19 Inducers; Cytochrome P-450 CYP2C9 Inducers; Midazolam; Ritonavir; Rifampin; Itraconazole; Hydroxyitraconazole
• Other Study ID Numbers: SIM0417-107

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

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