Study of Tolerability, Safety, and Pharmacokinetics of ZL-82 in Healthy Adult Subjects.

Study Overview
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Brief Summary
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ZL-82 is an oral janus kinase (JAK) inhibitor. In vitro biological mass spectrometry identification test proves that ZL-82 can selectively and irreversibly inhibit JAK3. It has obvious safety advantages, with a wide therapeutic window and controllable cardiotoxicity. This is also demonstrated from preliminary GLP-conditions of acute toxicity in SD rats and Beagle dogs. Results of 4-week long-term toxicity in Beagle dogs also support this notion. Therefore, ZL-82 has the potential to treat rheumatoid arthritis. It Used to relieve and heal swelling, pain, stiffness, and limited mobility that may be caused by rheumatoid arthritis.The drug is intended to be used in patients with RA to relieve and heal swelling, pain, stiffness, and limited mobility that may be caused by rheumatoid arthritis. Pharmacodynamic studies show that ZL-82 has a strong inhibitory effect on JAK3 with IC50 of 2.8 nM, and has no obvious inhibitory effect on JAK1, JAK2 and TYK2. Compared with the similar drug Tofacitinib, its inhibitory effect on JAK3 subtype is 1nM, but its inhibition IC50 for JAK1 subtype and JAK2 subtype are 112nM and 20nM, respectively.and its selectivity is 100-fold and 20-fold, respectively.Also, the selectivity multiples of ZL-82 were 100-fold and 20-fold than tofacitinib , respectively, which indicates that ZL-82 is more selective than the marketed Tofacitinib.This allows ZL-82 to precisely inhibit JAK kinase and block a series of cytokines in the downstream signaling pathway. And show significant effect on rheumatoid arthritis. The experimental results showed that in DTH and CIA models, 25, 50, 75, and 100 mg/kg of this variety could dose-dependently inhibit joint swelling in mice. Objectives of Study Main Purpose: To evaluate the tolerability, safety and pharmacokinetic characteristics of a single oral dose of ZL-82 tablets in healthy adult subjects; To explore the effect of eating on the PK of oral ZL-82 tablets in healthy adult subjects; To evaluate the tolerability, safety and pharmacokinetics of ZL-82 tablets after multiple oral administration in healthy adult subjects.

Official Title
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Phase I Clinical Study on the Tolerability, Safety and Pharmacokinetics of Single-dose Dose Escalation and Multiple-dose Oral ZL-82 Tablets in Healthy Adult Subjects

Conditions
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Rheumatoid Arthritis (RA), Inflammatory Bowel Disease - IBD1

Intervention / Treatment
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* Drug: ZL-82 12.5mg
* Drug: ZL-82 25mg
* Drug: ZL-82 50mg
* Drug: ZL-82 100mg
* Drug: ZL-82 200mg
* Drug: ZL-82 300mg
* Drug: ZL-82 450mg
* Drug: ZL-82 600mg


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy subjects, regardless of gender, 18 to 45 years old (including 18 and 45 years old) The weighing of male subjects ≥ 50kg, female subjects ≥ 45kg, and a body mass index (BMI) between 19 and 25kg/m2 (including boundary values) The medical history, physical examination, laboratory examination items and various tests and tests related to the trial before enrollment were normal or abnormal without clinical significance, and the clinical research doctor judged that they were qualified. Be able to understand the informed consent form, voluntarily participate in the trial and sign the informed consent form Exclusion Criteria: Allergic constitution, such as those who are known to be allergic to two or more substances, or those who are known to be allergic to JAK inhibitors or to the excipients contained in the test drug ALT and/or AST>1×ULN, TIB>1×ULN, GGT>1×ULN; Scr>1×ULN Major surgery within the 3 months prior to the trial or planning to undergo surgery during the trial Acute illness within 2 weeks prior to trial Have any serious diseases such as cardiovascular system, digestive system, urinary system, respiratory system, nervous system, immune system, endocrine system, malignant tumor, mental illness, etc. History of dysphagia or any gastrointestinal disease (or gastrointestinal resection, etc.) affecting drug absorption HIV antibody, Treponema pallidum antibody, hepatitis B surface antigen and hepatitis C antibody test are positive Positive urine drug screen (including morphine, methamphetamine, ketamine, MDMA, THC) Systolic blood pressure>140mmHg or diastolic blood pressure>90mmHg during the screening period; Blood donation or blood loss ≥400mL within 3 months, or blood transfusion; blood donation or blood loss ≥200mL within 1 month; Have special requirements for diet or cannot comply with the unified diet and corresponding regulations of the research center Alcoholics (alcoholism refers to drinking 60-degree white wine ≥10.5L or red wine ≥3.5L per week for more than 5 years), drinking a lot of coffee-containing beverages (more than 8 cups per day, 1 cup = 250ml) or heavy smoking (average > 20 sticks/day); Have used any prescription drugs (JAK inhibitors, etc.) that may have an effect on the test drug within 2 weeks; 4 weeks (28 days) before enrollment, strong inducers of liver metabolic enzymes was limit. ( such as omeprazole, barbiturates, carbamazepine, aminoglutamine, griseofulvin, carbamazepine, Phenytoin, Gluter, Rifampicin, Sulfinpyrazone, Roxithromycin, etc. ) Participate in clinical trials of other drugs or medical devices as subjects within 3 months Women who are pregnant or breastfeeding or women of childbearing age who have had unprotected sex with their partner within 14 days before the test; The subjects or their partners are unwilling to use non-drug contraceptive measures (such as total abstinence, condoms, IUDs, ligation, etc.) for contraception during the trial, or the subject and his partner has a pregnancy plan within 6 months of signing the informed consent; Not suitable to participate in the trial according to the judgment of the investigator.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 45 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: Non-Randomized
Intervention Model: Sequential Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ZL-82 12.5mg<br>2 case，The starting dose，Take the medicine once on D1 ，D1 through 7. | Drug: ZL-82 12.5mg<br>* 1 case,The starting dose,Take the medicine once on D1,D1-7.<br>|
| Experimental: ZL-82 25mg<br>8 case，The starting dose，Take the medicine once on D1 ，D1 through 7. | Drug: ZL-82 25mg<br>* 1 case,The starting dose,Take the medicine once on D1,D1-7.<br>|
| Experimental: ZL-82 50mg<br>8 case，The starting dose，Take the medicine once on D1 ，D1 through 7. | Drug: ZL-82 50mg<br>* 1 case,The starting dose,Take the medicine once on D1,D1-7.<br>|
| Experimental: ZL-82 100mg<br>8 case，The starting dose，Take the medicine once on D1 ，D1 through 7. | Drug: ZL-82 100mg<br>* 1 case,The starting dose,Take the medicine once on D1,D1-7.<br>|
| Experimental: ZL-82 200mg<br>8 case，The starting dose，Take the medicine once on D1 ，D1 through 7. | Drug: ZL-82 200mg<br>* 1 case,The starting dose,Take the medicine once on D1,D1-7.<br>|
| Experimental: ZL-82 300mg<br>8 case，The starting dose，Take the medicine once on D1 ，D1 through 7. | Drug: ZL-82 300mg<br>* 1 case,The starting dose,Take the medicine once on D1,D1-7.<br>|
| Experimental: ZL-82 450mg<br>8 case，The starting dose，Take the medicine once on D1 ，D1 through 7. | Drug: ZL-82 450mg<br>* 1 case,The starting dose,Take the medicine once on D1,D1-7.<br>|
| Experimental: ZL-82 600mg<br>8 case，The starting dose，Take the medicine once on D1 ，D1 through 7. | Drug: ZL-82 600mg<br>* 1 case,The starting dose,Take the medicine once on D1,D1-7.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetics (PK) of ZL-82：Cmax | Estimation of maximum observed plasma concentration | 24hours | 
| Pharmacokinetics (PK) of ZL-82：Tmax | Estimation of time to reach Cmax | 24hours | 
| Pharmacokinetics (PK) of ZL-82：AUC0-24h | Estimation of AUC from time zero to the last measured time point | 24hours | 
| Pharmacokinetics (PK) of ZL-82：AUC0-∞ | Estimation of AUC from time zero extrapolated to infinity | 24hours | 
| Pharmacokinetics (PK) of ZL-82：Vd | Estimation of apparent volume of distribution | 24hours | 
| Pharmacokinetics (PK) of ZL-82：t1/2 | Estimation of terminal elimination half-life | 24hours | 
| Pharmacokinetics (PK) of ZL-82：CLz/F | Estimation of clearance when dosed orally | 24hours | 
| Pharmacokinetics (PK) of ZL-82：Vz/F | Estimation of apparent volume of distribution when dosed orally | 24hours | 
| Pharmacokinetics (PK) of ZL-82：Kel | Estimation of the elimination rate constant of a drug in the body | 24hours |