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Safety and Pharmacokinetics of the Oral TYK2 Inhibitor PF-06826647: A Phase I, Randomized, Double-Blind, Placebo-Controlled, Dose-Escalation Study
- Source :
- Clinical and Translational Science, Clinical and Translational Science, Vol 14, Iss 2, Pp 671-682 (2021)
- Publication Year :
- 2020
-
Abstract
- Selective inhibition of tyrosine kinase 2 (TYK2) may offer therapeutic promise in inflammatory conditions, with its role in downstream pro-inflammatory cytokine signaling. In this first-in-human study, we evaluated the safety, tolerability, and pharmacokinetics (PK) of a novel TYK2 inhibitor, PF-06826647, in healthy participants. This phase I, randomized, double-blind, placebo-controlled, parallel-group study included two treatment periods (single ascending dose (SAD) and multiple ascending dose (MAD)) in healthy participants and a cohort of healthy Japanese participants receiving 400 mg q.d. or placebo in the MAD period (NCT03210961). Participants were randomly assigned to PF-06826647 or placebo (3:1). Participants received a single oral study drug dose of 3, 10, 30, 100, 200, 400, or 1,600 mg (SAD period), then 30, 100, 400, or 1,200 mg q.d. or 200 mg b.i.d. for 10 days (MAD period). Safety (adverse events (AEs), vital signs, and clinical laboratory parameters), tolerability, and PK were assessed. Overall, 69 participants were randomized to treatment, including six Japanese participants. No deaths, serious AEs, severe AEs, or AEs leading to dose reduction or temporary/permanent discontinuation were observed. All AEs were mild in severity. No clinically relevant laboratory abnormalities or changes in vital signs were detected. PF-06826647 was rapidly absorbed with a median time to maximum plasma concentration of 2 hours in a fasted state, with modest accumulation (< 1.5-fold) after multiple dosing and low urinary recovery. PF-06826647 was well-tolerated, with an acceptable safety profile for doses up to 1,200 mg q.d. for 10 days, supporting further testing in patients.
- Subjects :
- Adult
Male
030213 general clinical medicine
Urinary system
Vital signs
Administration, Oral
Placebo
030226 pharmacology & pharmacy
General Biochemistry, Genetics and Molecular Biology
Drug Administration Schedule
Article
Placebos
03 medical and health sciences
Young Adult
0302 clinical medicine
Pharmacokinetics
Double-Blind Method
Medicine
Humans
General Pharmacology, Toxicology and Pharmaceutics
Adverse effect
Protein Kinase Inhibitors
TYK2 Kinase
Dose-Response Relationship, Drug
business.industry
General Neuroscience
lcsh:Public aspects of medicine
Research
lcsh:RM1-950
lcsh:RA1-1270
General Medicine
Articles
Middle Aged
Healthy Volunteers
Discontinuation
lcsh:Therapeutics. Pharmacology
Tolerability
Anesthesia
Pyrazines
Cohort
Pyrazoles
Female
business
Subjects
Details
- ISSN :
- 17528062
- Volume :
- 14
- Issue :
- 2
- Database :
- OpenAIRE
- Journal :
- Clinical and translational science
- Accession number :
- edsair.doi.dedup.....34a1714f2fcc9f6c375b9f526e65ee8e