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

Chengdu Zenitar Biomedical Technology Co., Ltd1 个研究点分布在 1 个国家目标入组 69 人开始时间: 2023年4月9日最近更新: 2025年4月3日

适应症

干预措施

试验速览

阶段: 1 期
状态: 已完成
发起方: Chengdu Zenitar Biomedical Technology Co., Ltd
入组人数: 69
试验地点: 1
主要终点: Pharmacokinetics (PK) of ZL-82：Cmax

研究概览研究设计入排标准研究组 & 干预措施结局指标研究者研究点记录与标识符相似试验

研究概览

简要总结

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.

研究设计

研究类型: Interventional
分配方式: Randomized
干预模型: Sequential
主要目的: Other
盲法: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

入排标准

年龄范围: 18 Years 至 45 Years（Adult）
性别: All
接受健康志愿者: 是

入选标准

•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

排除标准

•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.

研究组 & 干预措施

ZL-82

Experimental

1 case，The starting dose，Take the medicine once on D1 ，D1 through 7.

干预措施: ZL-82 12.5mg (Drug)

ZL-82

Experimental

1 case，The starting dose，Take the medicine once on D1 ，D1 through 7.

干预措施: ZL-82 25mg (Drug)

ZL-82

Experimental

1 case，The starting dose，Take the medicine once on D1 ，D1 through 7.

干预措施: ZL-82 50mg (Drug)

ZL-82

Experimental

1 case，The starting dose，Take the medicine once on D1 ，D1 through 7.

干预措施: ZL-82 100mg (Drug)

ZL-82

Experimental

1 case，The starting dose，Take the medicine once on D1 ，D1 through 7.

干预措施: ZL-82 200mg (Drug)

ZL-82

Experimental

1 case，The starting dose，Take the medicine once on D1 ，D1 through 7.

干预措施: ZL-82 300mg (Drug)

ZL-82

Experimental

1 case，The starting dose，Take the medicine once on D1 ，D1 through 7.

干预措施: ZL-82 450mg (Drug)

ZL-82

Experimental

1 case，The starting dose，Take the medicine once on D1 ，D1 through 7.

干预措施: ZL-82 600mg (Drug)