A Phase I, Randomized, Double-Blind, Placebo-Controlled, Single Ascending Dose, Multiple Ascending Dose and Food Effect Study to Evaluate the Tolerance, Pharmacokinetics of Jaktinib, a New Selective Janus Kinase Inhibitor in Healthy Chinese Volunteers.

Jingrui Liu,Hewen Yin,Haijing Wei,Binhua Lv,Xiaoxue Zhu,Yanhua Ding

doi:10.3389/fphar.2020.604314

Jingrui Liu, Hewen Yin + Show 4 more

Open Access

https://doi.org/10.3389/fphar.2020.604314

Copy DOI

Abstract

Background: Jaktinib is a novel selective janus kinase 1/2 inhibitor. The phase I first-in-human study evaluated the tolerance and pharmacokinetics of jaktinib in healthy Chinese subjects. Methods: A randomized, double-blind, placebo-controlled study were designed. A total of 126 healthy subjects were enrolled into the single ascending dose, multiple ascending dose and food effect study. Safety endpoints included adverse events, abnormal vital signs, 12-lead ECGs, abdominal ultrasound, chest x-ray, physical examination and clinical laboratory tests. Blood, urine and feces samples were collected at predetermined time points for pharmacokinetic analysis of jaktinib, the metabolites ZG0244 and ZG0245, which are formed by oxidation or hydrolysis metabolic pathway, respectively. Results: Jaktinib was absorbed with a median time to peak plasma concentration of 1.25–3.5 h and was eliminated with a half-life of 2.952–9.040 h. Linear pharmacokinetic characteristic was presented over the dose range from 25 to 400 mg. No obvious accumulation was observed after multiple doses for 10 days. Administration after a high-fat breakfast significantly increased the absorption of jaktinib. The accumulated fraction of jaktinib and the determined metabolites excreted in urine and feces was 19.478%. Jaktinib was well tolerated in all single dose cohorts. In multiple dose cohorts, 200 mg q24 h method was evaluated as maximally tolerated dose. Neutropenia, diarrhea, dizziness and headache were the most frequently reported treatment related adverse events. No deaths, serious or Grade ≥4 adverse events was developed. Conclusion: Jaktinib was well tolerated when single dose ranging from 25 to 400 mg and multiple dose up to 200 mg q24 h. The safety and pharmacokinetic characteristics support the next trial in myelofibrosis patients.

Highlights

Myelofibrosis (MF), a category of chronic myeloproliferative neoplasms (MPN) that can present a de novo disease known as primary MF (PMF) or develop from other types of MPN including polycythemia vera (PV) and essential thrombocythemia (ET) (Mesa et al, 2016; Tefferi, 2016; Iurlo and Cattaneo, 2017; Rumi and Cazzola, 2017)
Exclusion criteria included smoking more than five cigarettes per day within the past 3 months; any clinically significant laboratory test or 12-lead ECG abnormality; history of drug abuse and/or alcoholism; intake of any other drugs, vitamins, or herbal medicine within 14 days or intake of any drugs known to influence the activity of drug metabolizing enzymes (CYP3A4, 1A2, 2D6 and 2C9) within 28 days before the first dose of the trial medication; pregnant or breastfeeding; multiple food and drug allergies
The study was approved by the Ethics Committee of the First Hospital of Jilin University, and conducted in accordance with the ethical principles originating in the Declaration of Helsinki version 2013 and in compliance with International Conference on Harmonization Good Clinical Practice Guidelines

Summary

Introduction

Myelofibrosis (MF), a category of chronic myeloproliferative neoplasms (MPN) that can present a de novo disease known as primary MF (PMF) or develop from other types of MPN including polycythemia vera (PV) and essential thrombocythemia (ET) (Mesa et al, 2016; Tefferi, 2016; Iurlo and Cattaneo, 2017; Rumi and Cazzola, 2017). It is a rare disease with clonal proliferation of pluripotent hematopoietic stem cells. The phase I first-in-human study evaluated the tolerance and pharmacokinetics of jaktinib in healthy Chinese subjects

Objectives

Methods

Results

Conclusion