PMID- 35506501
OWN - NLM
STAT- MEDLINE
DCOM- 20220704
LR  - 20220909
IS  - 2160-7648 (Electronic)
IS  - 2160-763X (Print)
IS  - 2160-763X (Linking)
VI  - 11
IP  - 7
DP  - 2022 Jul
TI  - A Phase 1 Study to Assess Mass Balance and Absolute Bioavailability of 
      Zimlovisertib in Healthy Male Participants Using a (14) C-Microtracer Approach.
PG  - 815-825
LID - 10.1002/cpdd.1109 [doi]
AB  - Zimlovisertib (PF-06650833) is a selective, reversible inhibitor of interleukin-1 
      receptor-associated kinase 4 (IRAK4) with anti-inflammatory effects. This phase 
      1, open-label, fixed-sequence, two-period, single-dose study aimed to evaluate 
      the mass balance and excretion rate of zimlovisertib in healthy male participants 
      using a (14) C-microtracer approach. All six participants received 300 mg (14) 
      C-zimlovisertib with lower radioactivity per mass unit orally in Period A, then 
      unlabeled zimlovisertib 300 mg orally and (14) C-zimlovisertib 135 mug 
      intravenously (IV) in Period B. Study objectives included extent and rate of 
      excretion of (14) C-zimlovisertib, pharmacokinetics, and safety and tolerability 
      of oral and IV zimlovisertib. Total radioactivity recovered in urine and feces 
      was 82.4% +/- 6.8% (urine 23.1% +/- 12.3%, feces 59.3% +/- 9.7%) in Period A. 
      Zimlovisertib was absorbed rapidly following oral administration, with the 
      fraction absorbed estimated to be 44%. Absolute oral bioavailability of the 
      300-mg dose was 17.4% (90% confidence interval 14.1%, 21.5%) using the 
      dose-normalized area under the concentration-time curve from time 0 to infinity. 
      There were no deaths, serious adverse events (AEs), severe AEs, discontinuations 
      or dose reductions due to AEs, and no clinically significant laboratory 
      abnormalities. These results demonstrate that zimlovisertib had low absolute oral 
      bioavailability and low absorption (<50%).
CI  - (c) 2022 The Authors. Clinical Pharmacology in Drug Development published by Wiley 
      Periodicals LLC on behalf of American College of Clinical Pharmacology.
FAU - Singh, Ravi Shankar P
AU  - Singh RSP
AD  - Pfizer Inc, Cambridge, Massachusetts, USA.
FAU - Dowty, Martin E
AU  - Dowty ME
AD  - Pfizer Inc, Cambridge, Massachusetts, USA.
FAU - Salganik, Mikhail
AU  - Salganik M
AD  - Pfizer Inc, Cambridge, Massachusetts, USA.
FAU - Brodfuehrer, Joanne I
AU  - Brodfuehrer JI
AD  - Pfizer Inc, Cambridge, Massachusetts, USA.
FAU - Walker, Gregory S
AU  - Walker GS
AD  - Pfizer Inc, Groton, Connecticut, USA.
FAU - Sharma, Raman
AU  - Sharma R
AD  - Pfizer Inc, Groton, Connecticut, USA.
FAU - Beebe, Jean S
AU  - Beebe JS
AD  - Pfizer Inc, Cambridge, Massachusetts, USA.
FAU - Danto, Spencer I
AU  - Danto SI
AD  - Pfizer Inc, Cambridge, Massachusetts, USA.
LA  - eng
PT  - Clinical Trial, Phase I
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20220504
PL  - United States
TA  - Clin Pharmacol Drug Dev
JT  - Clinical pharmacology in drug development
JID - 101572899
SB  - IM
MH  - Administration, Oral
MH  - *Biological Availability
MH  - Feces
MH  - Healthy Volunteers
MH  - Humans
MH  - Male
PMC - PMC9322294
OTO - NOTNLM
OT  - IRAK4 inhibitor
OT  - bioavailability
OT  - mass balance
OT  - microtracer accelerator mass spectrometry
OT  - zimlovisertib
COIS- All authors are employees and may hold stock in Pfizer Inc. Medical writing 
      support, under the guidance of the authors, was provided by Neil Cockburn, BSc, 
      and Molly MacFadyen, MSc, at CMC Connect, McCann Health Medical Communications, 
      and was funded by Pfizer Inc, New York, NY in accordance with Good Publication 
      Practice (GPP3) guidelines (Ann Intern Med. 2015;163[6]:461-464).
EDAT- 2022/05/05 06:00
MHDA- 2022/07/06 06:00
PMCR- 2022/07/26
CRDT- 2022/05/04 06:34
PHST- 2021/08/19 00:00 [received]
PHST- 2022/04/04 00:00 [accepted]
PHST- 2022/05/05 06:00 [pubmed]
PHST- 2022/07/06 06:00 [medline]
PHST- 2022/05/04 06:34 [entrez]
PHST- 2022/07/26 00:00 [pmc-release]
AID - CPDD1109 [pii]
AID - 10.1002/cpdd.1109 [doi]
PST - ppublish
SO  - Clin Pharmacol Drug Dev. 2022 Jul;11(7):815-825. doi: 10.1002/cpdd.1109. Epub 
      2022 May 4.