PMID- 34107172
OWN - NLM
STAT- MEDLINE
DCOM- 20220404
LR  - 20220405
IS  - 2160-7648 (Electronic)
IS  - 2160-763X (Linking)
VI  - 10
IP  - 12
DP  - 2021 Dec
TI  - Effect of Varying Degrees of Hepatic Impairment on the Pharmacokinetics of 
      Omecamtiv Mecarbil.
PG  - 1442-1451
LID - 10.1002/cpdd.969 [doi]
AB  - Omecamtiv mecarbil (OM) is a novel selective cardiac myosin activator under 
      investigation for the treatment of heart failure with reduced ejection fraction. 
      OM is primarily eliminated via metabolism mediated by multiple cytochrome P450 
      enzymes. This phase 1 single-dose, multicenter, open-label, nonrandomized study 
      evaluated the pharmacokinetics (PK) of OM and major metabolites M3 and M4, 
      safety, and tolerability following oral administration of a single dose of 25-mg 
      MR tablet in subjects with mild (n = 6) or moderate (n = 6) hepatic impairment 
      (according to Child-Pugh classification) versus subjects with normal hepatic 
      function (n = 6). Relative to subjects with normal hepatic function, for subjects 
      with mild or moderate hepatic impairment, OM AUC(inf) was 103.2% (90%CI, 
      58.0%-183.6%) and 94.8% (90%CI, 54.7%-164.1%), respectively, and OM C(max) was 
      126.8% (90%CI, 85.7%-187.7%) and 117.3% (90%CI, 80.7%-170.5%), respectively. 
      Exposures to M3 were similar across groups, whereas slightly lower exposures were 
      observed for M4 with worsening hepatic function. The OM, M3, and M4 t(max) and 
      t(1/2) values were similar between groups. There were no serious adverse events 
      (AEs) or treatment-related treatment-emergent AEs. Overall, OM, M3, and M4 PK 
      were not meaningfully affected by mild or moderate hepatic impairment, suggesting 
      the same dosing strategy can be used in subjects with mild or moderate hepatic 
      impairment.
CI  - (c) 2021, The American College of Clinical Pharmacology.
FAU - Trivedi, Ashit
AU  - Trivedi A
AD  - Amgen Inc., Thousand Oaks, California, USA.
FAU - Oberoi, Rajneet K
AU  - Oberoi RK
AD  - Amgen Inc., Thousand Oaks, California, USA.
FAU - Mackowski, Mia
AU  - Mackowski M
AD  - Amgen Inc., Thousand Oaks, California, USA.
FAU - Jafarinasabian, Pegah
AU  - Jafarinasabian P
AD  - Amgen Inc., Thousand Oaks, California, USA.
FAU - Zhang, Hanze
AU  - Zhang H
AD  - Amgen Inc., Thousand Oaks, California, USA.
FAU - Flach, Stephen
AU  - Flach S
AD  - Covance Inc., Madison, Wisconsin, USA.
FAU - Hutton, Shauna
AU  - Hutton S
AD  - Amgen Inc., Thousand Oaks, California, USA.
FAU - Abbasi, Siddique
AU  - Abbasi S
AD  - Amgen Inc., Thousand Oaks, California, USA.
FAU - Dutta, Sandeep
AU  - Dutta S
AD  - Amgen Inc., Thousand Oaks, California, USA.
FAU - Lee, Edward
AU  - Lee E
AD  - Amgen Inc., Thousand Oaks, California, USA.
LA  - eng
PT  - Journal Article
PT  - Multicenter Study
PT  - Research Support, Non-U.S. Gov't
DEP - 20210609
PL  - United States
TA  - Clin Pharmacol Drug Dev
JT  - Clinical pharmacology in drug development
JID - 101572899
RN  - 0 (Tablets)
RN  - 2M19539ERK (omecamtiv mecarbil)
RN  - 8W8T17847W (Urea)
SB  - IM
MH  - Administration, Oral
MH  - Area Under Curve
MH  - Humans
MH  - Tablets
MH  - *Urea/adverse effects/analogs & derivatives
OTO - NOTNLM
OT  - heart failure
OT  - hepatic impairment
OT  - metabolism
OT  - omecamtiv mecarbil
OT  - pharmacokinetics
EDAT- 2021/06/10 06:00
MHDA- 2022/04/05 06:00
CRDT- 2021/06/09 17:38
PHST- 2021/02/26 00:00 [received]
PHST- 2021/05/03 00:00 [accepted]
PHST- 2021/06/10 06:00 [pubmed]
PHST- 2022/04/05 06:00 [medline]
PHST- 2021/06/09 17:38 [entrez]
AID - 10.1002/cpdd.969 [doi]
PST - ppublish
SO  - Clin Pharmacol Drug Dev. 2021 Dec;10(12):1442-1451. doi: 10.1002/cpdd.969. Epub 
      2021 Jun 9.