The Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of a TYK2/JAK1 Inhibitor (PF-06700841) in Healthy Subjects and Patients With Plaque Psoriasis.

Abstract

The safety, tolerability, pharmacokinetics, and pharmacodynamics of PF-06700841 were assessed in a randomized, double-blind, placebo-controlled, single- and multiple-dose escalation, parallel-group study in healthy subjects and patients with plaque psoriasis. The single ascending dose (1, 3, 10, 30, 100, or 200 mg) and multiple ascending dose (MAD; PF-06700841; up to 175 mg once daily or 50 mg twice daily for 10 days) periods included 54 healthy participants. In addition, 30 patients with psoriasis received PF-06700841 30 or 100 mg or placebo once daily for 28 days. Single PF-06700841 doses were rapidly absorbed, with peak plasma concentrations ≤ 1 hour, proportional exposure up to 100 mg, and mean half-life 3.8-7.5 hours. On day 10 of MAD, plasma concentrations peaked at ≤1.5 hours postdose (10-175 mg once daily). Elimination half-life was 4.9-10.7 hours; steady state was reached by day 8. In psoriasis patients on day 28, peak plasma concentrations occurred at 1-2 hours. Biomarkers IP-10 and high-sensitivity C-reactive protein were reduced and returned to near baseline levels after dosing. Maximal mean percent change from baseline in the Psoriasis Area and Severity Index scores for PF-06700841 30 mg once daily and 100 mg once daily were -67.92% and -96.31%, respectively, in week 4. All adverse events were mild/moderate. PF-06700841 was safe and well tolerated up to 200 mg once daily in healthy subjects and 100 mg once daily in patients with psoriasis, suggesting potential therapeutic utility in plaque psoriasis and other inflammatory diseases.

• Authors: Christopher Banfield, Matthew Scaramozza, Weidong Zhang, Elizabeth Kieras, Karen M Page, Andrew Fensome, Michael Vincent, Martin E Dowty, Kosalaram Goteti, Peter J Winkle, Elena Peeva
• Journal: Journal of clinical pharmacology (J Clin Pharmacol) Vol. 58 Issue 4 Pg. 434-447 (04 2018) ISSN: 1552-4604 [Electronic] England
• PMID: 29266308 (Publication Type: Clinical Trial, Phase I, Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
• Copyright: © 2017, The American College of Clinical Pharmacology.

Chemical References

• Protein Kinase Inhibitors
• Pyrazoles
• Pyrimidines
• PF-06700841
• C-Reactive Protein
• JAK1 protein, human
• Janus Kinase 1
• TYK2 Kinase
• TYK2 protein, human

Topics

• Adolescent
• Adult
• Aged
• Biological Availability
• Blood Cell Count
• C-Reactive Protein (analysis)
• Double-Blind Method
• Female
• Healthy Volunteers
• Humans
• Janus Kinase 1 (antagonists & inhibitors)
• Male
• Middle Aged
• Protein Kinase Inhibitors (administration & dosage, adverse effects, blood, pharmacokinetics)
• Psoriasis (blood, drug therapy)
• Pyrazoles (administration & dosage, adverse effects, blood, pharmacokinetics)
• Pyrimidines (administration & dosage, adverse effects, blood, pharmacokinetics)
• TYK2 Kinase (antagonists & inhibitors)
• Young Adult