PMID- 33290616
OWN - NLM
STAT- MEDLINE
DCOM- 20211208
LR  - 20240331
IS  - 1752-8062 (Electronic)
IS  - 1752-8054 (Print)
IS  - 1752-8054 (Linking)
VI  - 14
IP  - 2
DP  - 2021 Mar
TI  - Safety and Pharmacokinetics of the Oral TYK2 Inhibitor PF-06826647: A Phase I, 
      Randomized, Double-Blind, Placebo-Controlled, Dose-Escalation Study.
PG  - 671-682
LID - 10.1111/cts.12929 [doi]
AB  - 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.
CI  - (c) 2020 Pfizer Inc. Clinical and Translational Science published by Wiley 
      Periodicals LLC on behalf of the American Society for Clinical Pharmacology and 
      Therapeutics.
FAU - Singh, Ravi Shankar P
AU  - Singh RSP
AD  - Pfizer Inc, Cambridge, Massachusetts, USA.
FAU - Pradhan, Vivek
AU  - Pradhan V
AD  - Pfizer Inc, Cambridge, Massachusetts, USA.
FAU - Roberts, Erika S
AU  - Roberts ES
AD  - Pfizer Inc, Cambridge, Massachusetts, USA.
FAU - Scaramozza, Matthew
AU  - Scaramozza M
AD  - Pfizer Inc, Cambridge, Massachusetts, USA.
FAU - Kieras, Elizabeth
AU  - Kieras E
AD  - Pfizer Inc, Cambridge, Massachusetts, USA.
FAU - Gale, Jeremy D
AU  - Gale JD
AD  - Pfizer Inc, Cambridge, Massachusetts, USA.
FAU - Peeva, Elena
AU  - Peeva E
AD  - Pfizer Inc, Cambridge, Massachusetts, USA.
FAU - Vincent, Michael S
AU  - Vincent MS
AD  - Pfizer Inc, Cambridge, Massachusetts, USA.
FAU - Banerjee, Anindita
AU  - Banerjee A
AD  - Pfizer Inc, Cambridge, Massachusetts, USA.
FAU - Fensome, Andrew
AU  - Fensome A
AD  - Pfizer Inc, Cambridge, Massachusetts, USA.
FAU - Dowty, Martin E
AU  - Dowty ME
AD  - Pfizer Inc, Cambridge, Massachusetts, USA.
FAU - Winkle, Peter
AU  - Winkle P
AD  - Anaheim Clinical Trials, Anaheim, California, USA.
FAU - Tehlirian, Christopher
AU  - Tehlirian C
AD  - Pfizer Inc, Cambridge, Massachusetts, USA.
LA  - eng
PT  - Clinical Trial, Phase I
PT  - Journal Article
PT  - Randomized Controlled Trial
PT  - Research Support, Non-U.S. Gov't
DEP - 20201208
PL  - United States
TA  - Clin Transl Sci
JT  - Clinical and translational science
JID - 101474067
RN  - 0 (Placebos)
RN  - 0 (Protein Kinase Inhibitors)
RN  - 0 (Pyrazines)
RN  - 0 (Pyrazoles)
RN  - EC 2.7.10.2 (TYK2 Kinase)
RN  - EC 2.7.10.2 (TYK2 protein, human)
RN  - HY5SOV7O0Q (ropsacitinib)
SB  - IM
MH  - Administration, Oral
MH  - Adult
MH  - Dose-Response Relationship, Drug
MH  - Double-Blind Method
MH  - Drug Administration Schedule
MH  - Female
MH  - Healthy Volunteers
MH  - Humans
MH  - Male
MH  - Middle Aged
MH  - Placebos/administration & dosage/adverse effects
MH  - *Protein Kinase Inhibitors/administration & dosage/adverse 
      effects/pharmacokinetics
MH  - *Pyrazines/administration & dosage/adverse effects/pharmacokinetics
MH  - *Pyrazoles/administration & dosage/adverse effects/pharmacokinetics
MH  - TYK2 Kinase/*antagonists & inhibitors
MH  - Young Adult
PMC - PMC7993274
COIS- R.S.P.S., V.P., E.S.R., M.S., E.K., J.D.G., E.P., M.S.V., A.B., A.F., M.E.D., and 
      C.T. were employees of Pfizer Inc at the time the study was conducted. R.S.P.S., 
      V.P., E.S.R., M.S., E.K., E.P., M.S.V., J.D.G., A.B., A.F., M.E.D., and C.T. hold 
      stock in Pfizer Inc. P.W. is a full-time employee of Anaheim Clinical Trials.
EDAT- 2020/12/09 06:00
MHDA- 2021/12/15 06:00
PMCR- 2021/03/01
CRDT- 2020/12/08 17:19
PHST- 2020/08/24 00:00 [received]
PHST- 2020/10/25 00:00 [accepted]
PHST- 2020/12/09 06:00 [pubmed]
PHST- 2021/12/15 06:00 [medline]
PHST- 2020/12/08 17:19 [entrez]
PHST- 2021/03/01 00:00 [pmc-release]
AID - CTS12929 [pii]
AID - 10.1111/cts.12929 [doi]
PST - ppublish
SO  - Clin Transl Sci. 2021 Mar;14(2):671-682. doi: 10.1111/cts.12929. Epub 2020 Dec 8.