To Evaluate the Pharmacokinetic Effects of TQD3606 for Injection in Healthy Adult Subjects

Study Overview
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Brief Summary
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TQD3606 is a fixed-dose combination of meropenem and avibatam. This study is a phase I clinical study to evaluate the safety, tolerability and pharmacokinetic characteristics of TQD3606 injection in a single center, randomized, double-blind, placebo-controlled, single and multiple administration in healthy subjects, and to explore the excretion of TQD3606 in urine. To evaluate the tolerability and safety of injectable TQD3606 after single and multiple dosing in healthy subjects.

Official Title
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Phase I Clinical Study to Evaluate the Safety, Tolerability, and Pharmacokinetic Characteristics of Injectable TQD3606 in a Single Center, Randomized, Double-blind, Placebo-controlled, Single, Multiple Dosing in Healthy Subjects, and to Explore Urinary Excretion of the Product

Conditions
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Infections

Intervention / Treatment
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* Drug: The injectable TQD3606
* Drug: meropenem
* Drug: Avibactam Sodium
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 1 Signed the informed consent before the test and fully understood the test content, process and possible adverse reactions; 2 Able to complete the research according to the requirements of the test plan; 3 Subjects aged between 18 and 55 (including 18 and 55); 4 Body mass index (BMI) ≥ 18 and ≤ 28kg/m2, with male weight ≥ 50 kg and female weight ≥ 45 kg; 5 Health status: No mental disorders, no history of cardiovascular system, nervous system, respiratory system, digestive system, urinary system, endocrine system and metabolic abnormalities; 6 Subjects had no pregnancy plan and voluntarily used effective contraceptive measures for at least 6 months from 2 weeks before self-medication to the last use of study medication. Exclusion Criteria: 1 Previous neuropsychiatric system, respiratory system, cardiovascular system, digestive system, hemolymph system, liver and kidney dysfunction, endocrine system, musculoskeletal system disease or other diseases, and the investigator judged that the previous history may affect drug metabolism or safety; 2 Known allergic history to meropenem or avitabtam, known history of anaphylactic shock to penicillin, cephalosporins, carbapenems and other β -lactam antibiotics or other severe allergic reactions (such as bullous epidermolysis atrophic dermatitis, exudative dermatitis); 3 Allergic constitution, including allergy to food and other drugs; 4 Persons with a history of epilepsy or central nervous system dysfunction; 5 Those with definite chronic headache or chronic diarrhea in the past; 6 Changes in QT interval or QT Corrected (QTc) > 450ms were considered clinically significant by researchers; 7 The creatinine clearance rate was less than 50ml/min; 8 Taking any prescription, over-the-counter, vitamin products or herbal medicine within 2 weeks prior to screening; 9 Abnormal and clinically significant laboratory tests during screening period; 10 Blood donation or significant blood loss within 3 months prior to taking the study drug (>450 ml); 11 Participated in any drug clinical trials within 3 months prior to taking the study drug; 12 Heavy smokers (5 cigarettes or more per day) within 3 months prior to screening; 13 Have a history of drug and/or alcohol abuse (14 units of alcohol per week: 1 unit =360mL beer or 45mL 40% spirits or 150mL wine); 14 Urine drug test positive or have a history of drug abuse or drug use in the past five years; 15 Unable to tolerate venipuncture blood collection or poor vascular condition; 16 Have taken a special diet (including dragon fruit, mango, grapefruit, grapefruit juice and/or xanthine diet) within 2 weeks prior to the trial; 17 Consuming chocolate, caffeinated coffee or tea within 48 hours before the trial; 18 Have taken any alcoholic food or beverage within 48 hours prior to the test; 19 The subject cannot complete the test due to personal reasons; 20 Conditions considered unsuitable for inclusion by other researchers.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

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: Other
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: The injectable TQD3606<br>received a single dose of 0.75g TQD3606 for injection | Drug: The injectable TQD3606<br>* TQD3606 is a fixed-dose combination of meropenem and avibatam.<br>|
| Active Comparator: The injectable TQD3606+ meropenem<br>First, a single dose of 0.5g of meropenem for injection was administered for 0.5h intravenous infusion; after washout for at least 2 days, 0.75g of TQD3606 for injection was administered for 1h intravenous infusion; for at least 2 days of washout, 0.75g was administered A single dose of TQD3606 for injection was administered for 2 hours, and the elution time was at least 2 days. Finally, a single dose of 0.75 g of TQD3606 for injection was administered, and the duration of intravenous infusion was 3 hours. | Drug: The injectable TQD3606<br>* TQD3606 is a fixed-dose combination of meropenem and avibatam.<br>Drug: meropenem<br>* Meropenem is a carbapenem antibiotic<br>|
| Active Comparator: The injectable TQD3606+ meropenem+ Avibactam Sodium<br>According to the random table, they were divided into two groups, A and B, Group A was given 1.0g meropenem for injection (Mepin) in the first cycle, and 0.5g avibactam sodium for injection in the second cycle. The third cycle was given 1.5g TQD3606 for injection; group B was given 0.5g avibactam sodium for injection in the first cycle, 1.0g meropenem (Mepin) for injection in the second cycle, and 1.5g for injection in the third cycle TQD3606. | Drug: The injectable TQD3606<br>* TQD3606 is a fixed-dose combination of meropenem and avibatam.<br>Drug: meropenem<br>* Meropenem is a carbapenem antibiotic<br>Drug: Avibactam Sodium<br>* Avibactam is beta-lactamase inhibitor.<br>|
| Experimental: The injectable TQD3606-1<br>First, 0.75g TQD3606 for injection was administered multiple times (Dosing every 8 hours, 3 consecutive doses), and at least 2 days were washed out after the last dose; then 1.125g TQD3606 for injection was administered multiple times (Dosing every 12 hours, 2 consecutive doses) times), wash out at least 2 days after the last administration; finally, a single administration of 2.25 g of TQD3606 for injection (Dosing every 12 hours, once administered). Intravenous infusion for 3 hours. | Drug: The injectable TQD3606<br>* TQD3606 is a fixed-dose combination of meropenem and avibatam.<br>|
| Placebo Comparator: The injectable TQD3606/ Placebo<br>First, a single dose of 3.0g TQD3606 for injection/placebo was administered, intravenous infusion for 3hours, and washout for at least 3 days; then multiple doses of 3.0g TQD3606 for injection/placebo were administered (Dosing every 8 hours, 10 consecutive doses) , the intravenous infusion duration is 3hours. | Drug: The injectable TQD3606<br>* TQD3606 is a fixed-dose combination of meropenem and avibatam.<br>Drug: Placebo<br>* It is a placebo.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Concentration (Cmax) | Maximum Concentration | 1 hour before administration，to 24 hours after administration. | 
| Area under the plasma concentration-time curve from initial dosing to 24 hours (AUC0-24) | Area under the plasma concentration-time curve from initial dosing to 24 hours | 1 hour before administration，to 24 hours after administration. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to maximum concentration following drug administration (Tmax) | Time to maximum concentration following drug administration | 1 hour before administration，to 24 hours after administration. | 
| Apparent terminal elimination half-life following drug administration (t1/2) | Apparent terminal elimination half-life following drug administration | 1 hour before administration，to 24 hours after administration. | 
| Area under plasma concentration-time curve from first dosing to last measurable concentration point (AUC0-t) | Area under plasma concentration-time curve from first dosing to last measurable concentration point | 1 hour before administration，to 24 hours after administration. | 
| The amount of drug excreted through urine 24 hours after administration (Ae0-24) | The amount of drug excreted through urine 24 hours after administration | 1 hour before administration，to 24 hours after administration. | 
| Cumulative excretion rate of drugs through urine | Cumulative excretion rate of drugs through urine | 1 hour before administration，to 24 hours after administration. | 
| The total clearance (CLt) The total clearance (CLt) | The total clearance | 1 hour before administration，to 24 hours after administration. | 
| Renal clearance (CLr) | Renal clearance | 1 hour before administration，to 24 hours after administration. | 
| Elimination rate constant(λz) | Elimination rate constant | 1 hour before administration，to 24 hours after administration. | 
| Apparent volume of distribution (Vd/F) | Apparent volume of distribution | 1 hour before administration，to 24 hours after administration. | 
| Mean residence time (MRT) | Mean residence time | 1 hour before administration，to 24 hours after administration. | 
| Valley concentration (Cmin,ss) | Valley concentration | Within 60 minutes before 8th to 10th administration and 24 hours after 10th administration | 
| Accumulation index | Accumulation index | Within 60 minutes before 8th to 10th administration and 24 hours after 10th administration | 
| Adverse event rate | The occurrence of all adverse events (AEs), serious adverse events (SAEs) and treatment-related adverse events (TEAEs). | Baseline up to 24 hours after administration | 
| Number of participants with treatment-related adverse events as assessed by CTCAE v5.0 | Monitor the safety indicators of subjects during the trial | Baseline up to 24 hours after administration | 
| Body temperature | Monitor the safety indicators of subjects during the trial | 1 hour before administration and 24 hours after administration | 
| Pulse | Monitor the safety indicators of subjects during the trial | 1 hour before administration and 24 hours after administration | 
| Systolic and diastolic blood pressure | Monitor the safety indicators of subjects during the trial | 1 hour before administration and 24 hours after administration | 
| Number of participants with abnormal laboratory test results | Monitor the safety indicators of subjects during the trial | Baseline up to 24 hours after administration |