PMID- 37705327
OWN - NLM
STAT- MEDLINE
DCOM- 20231023
LR  - 20231023
IS  - 2163-8306 (Electronic)
IS  - 2163-8306 (Linking)
VI  - 12
IP  - 10
DP  - 2023 Oct
TI  - Model based assessment of food and acid reducing agent effects on oral absorption 
      of mezigdomide (CC-92480), a novel cereblon E3 ligase modulator.
PG  - 1473-1484
LID - 10.1002/psp4.13024 [doi]
AB  - Mezigdomide is a novel cereblon E3 ligase modulator (CELMoD) agent with enhanced 
      autonomous cell-killing activity in multiple myeloma (MM) cells, and promising 
      immunomodulatory and antitumor activity in patients with MM. We developed a 
      population pharmacokinetics (PKs) model for mezigdomide in healthy subjects 
      (HSs), and quantified effects of high-fat meal and proton pump inhibitor (PPI) on 
      human disposition parameters. Plasma concentrations from 64 HS in two phase I 
      clinical studies (NCT03803644 and NCT04211545) were used to develop a population 
      PK model. The HSs received single oral doses of 0.4-3.2 mg mezigdomide with full 
      PK profiles collected. A two-compartment linear PK model with first-order 
      absorption and lag time best described mezigdomide PK profiles in HSs. The 
      population PK parameters of absorption rate constant, lag time, central volume of 
      distribution, clearance, peripheral volume of distribution, and 
      intercompartmental clearance were estimated to be 1.18 h(-1) (interoccasion 
      variability [IOV]: 65%), 0.423 h (IOV: 31%), 440 L (interindividual variability 
      [IIV]: 63%), 35.1 L/h (IIV: 40%), 243 L (IIV: 26%), and 36.8 L/h (IIV: 26%), 
      respectively. High-fat meal increased oral bioavailability by ~30% and PPI 
      co-administration decreased oral bioavailability by ~64%. Mezigdomide 
      demonstrated a linear dose-exposure relationship in HSs. The PK model suggests a 
      modest effect of high-fat meal, and a substantial effect of PPIs on mezigdomide 
      oral bioavailability. This population PK model enables data integration across 
      studies to identify important covariate effects and is being used to guide dose 
      selection in clinical study designs for mezigdomide in patients with MM.
CI  - (c) 2023 Bristol Myers Squibb. CPT: Pharmacometrics & Systems Pharmacology 
      published by Wiley Periodicals LLC on behalf of American Society for Clinical 
      Pharmacology and Therapeutics.
FAU - Wu, Fan
AU  - Wu F
AD  - Bristol Myers Squibb, Princeton, New Jersey, USA.
FAU - Liu, Liangang
AU  - Liu L
AD  - Bristol Myers Squibb, Princeton, New Jersey, USA.
FAU - Gaudy, Allison
AU  - Gaudy A
AD  - Bristol Myers Squibb, Princeton, New Jersey, USA.
FAU - Wang, Xiaomin
AU  - Wang X
AD  - Bristol Myers Squibb, Princeton, New Jersey, USA.
FAU - Carayannopoulos, Leon
AU  - Carayannopoulos L
AD  - Bristol Myers Squibb, Princeton, New Jersey, USA.
FAU - Pourdehnad, Michael
AU  - Pourdehnad M
AD  - Bristol Myers Squibb, Princeton, New Jersey, USA.
FAU - Lamba, Manisha
AU  - Lamba M
AD  - Bristol Myers Squibb, Princeton, New Jersey, USA.
LA  - eng
SI  - ClinicalTrials.gov/NCT03803644
SI  - ClinicalTrials.gov/NCT04211545
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20230913
PL  - United States
TA  - CPT Pharmacometrics Syst Pharmacol
JT  - CPT: pharmacometrics & systems pharmacology
JID - 101580011
RN  - 0 (Reducing Agents)
RN  - 0 (Immunosuppressive Agents)
SB  - IM
MH  - Humans
MH  - *Reducing Agents
MH  - Administration, Oral
MH  - *Immunosuppressive Agents
PMC - PMC10583261
COIS- F.W., L.L., A.G., X.W., L.C., M.P., and M.L. are employees and stockholders of 
      Bristol Myers Squibb.
EDAT- 2023/09/14 06:42
MHDA- 2023/10/23 00:44
PMCR- 2023/09/13
CRDT- 2023/09/14 02:11
PHST- 2023/06/16 00:00 [revised]
PHST- 2023/03/02 00:00 [received]
PHST- 2023/07/24 00:00 [accepted]
PHST- 2023/10/23 00:44 [medline]
PHST- 2023/09/14 06:42 [pubmed]
PHST- 2023/09/14 02:11 [entrez]
PHST- 2023/09/13 00:00 [pmc-release]
AID - PSP413024 [pii]
AID - 10.1002/psp4.13024 [doi]
PST - ppublish
SO  - CPT Pharmacometrics Syst Pharmacol. 2023 Oct;12(10):1473-1484. doi: 
      10.1002/psp4.13024. Epub 2023 Sep 13.