PMID- 35730131
OWN - NLM
STAT- MEDLINE
DCOM- 20220914
LR  - 20230124
IS  - 1752-8062 (Electronic)
IS  - 1752-8054 (Print)
IS  - 1752-8054 (Linking)
VI  - 15
IP  - 9
DP  - 2022 Sep
TI  - Investigation of CYP3A induction by PF-05251749 in early clinical development: 
      comparison of linear slope physiologically based pharmacokinetic prediction and 
      biomarker response.
PG  - 2184-2194
LID - 10.1111/cts.13352 [doi]
AB  - PF-05251749 is a dual inhibitor of casein kinase 1 delta/epsilon under clinical development 
      to treat disruption of circadian rhythm in Alzheimer's and Parkinson's diseases. 
      In vitro, PF-05251749 (0.3-100 muM) induced CYP3A in cryopreserved human 
      hepatocytes, demonstrating non-saturable, dose-dependent CYP3A mRNA increases, 
      with induction slopes in the range 0.036-0.39 muM(-1) . In a multiple-dose study 
      (B8001002) in healthy participants, CYP3A activity was explored by measuring 
      changes in 4beta-hydroxycholesterol/cholesterol ratio. Following repeated oral 
      administration of PF-05251749, up to 400 mg q.d., no significant changes were 
      observed in 4beta-hydroxycholesterol/cholesterol ratio; this ratio increased 
      significantly (~1.5-fold) following administration of PF-05251749 at 750 mg q.d., 
      suggesting potential CYP3A induction at this dose. Physiologically based 
      pharmacokinetic (PBPK) models were developed to characterize the observed 
      clinical pharmacokinetics (PK) of PF-05251749 at 400 and 750 mg q.d.; the PBPK 
      induction model was calibrated using the in vitro linear fit induction slope, 
      with rifampin as reference compound (Ind(max)  = 8, EC(50)  = 0.32 muM). Clinical 
      trial simulation following co-administration of PF-05251749, 400 mg q.d. with 
      oral midazolam 2 mg, predicted no significant drug interaction risk. PBPK model 
      predicted weak drug interaction following co-administration of PF-05251749, 
      750 mg q.d. with midazolam 2 mg. In conclusion, good agreement was obtained 
      between CYP3A drug interaction risk predicted using linear-slope PBPK model and 
      exploratory biomarker trends. This agreement between two orthogonal approaches 
      enabled assessment of drug interaction risks of PF-05251749 in early clinical 
      development, in the absence of a clinical drug-drug interaction study.
CI  - (c) 2022 The Authors. Clinical and Translational Science published by Wiley 
      Periodicals LLC on behalf of American Society for Clinical Pharmacology and 
      Therapeutics.
FAU - Lin, Jian
AU  - Lin J
AD  - Medicine Design Pharmacokinetics, Pharmacodynamics, and Metabolism, Worldwide 
      Research, Development and Medical, Pfizer Inc., Groton, Connecticut, USA.
FAU - Gaudreault, Francois
AU  - Gaudreault F
AD  - Clinical Pharmacology, Early Clinical Development, Worldwide Research, 
      Development and Medical, Pfizer Inc., Cambridge, Massachusetts, USA.
FAU - Johnson, Nathaniel
AU  - Johnson N
AD  - Medicine Design Pharmacokinetics, Pharmacodynamics, and Metabolism, Worldwide 
      Research, Development and Medical, Pfizer Inc., Groton, Connecticut, USA.
FAU - Lin, Zhiwu
AU  - Lin Z
AD  - Medicine Design Pharmacokinetics, Pharmacodynamics, and Metabolism, Worldwide 
      Research, Development and Medical, Pfizer Inc., Groton, Connecticut, USA.
FAU - Nouri, Parya
AU  - Nouri P
AD  - Clinical Assay Group, Global Product Development, Pfizer Inc., Cambridge, 
      Massachusetts, USA.
FAU - Goosen, Theunis C
AU  - Goosen TC
AD  - Medicine Design Pharmacokinetics, Pharmacodynamics, and Metabolism, Worldwide 
      Research, Development and Medical, Pfizer Inc., Groton, Connecticut, USA.
FAU - Sawant-Basak, Aarti
AU  - Sawant-Basak A
AD  - Clinical Pharmacology, Early Clinical Development, Worldwide Research, 
      Development and Medical, Pfizer Inc., Cambridge, Massachusetts, USA.
LA  - eng
SI  - ClinicalTrials.gov/NCT02691702
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20220702
PL  - United States
TA  - Clin Transl Sci
JT  - Clinical and translational science
JID - 101474067
RN  - 0 (Biomarkers)
RN  - 0 (Cytochrome P-450 CYP3A Inducers)
RN  - EC 1.14.14.1 (Cytochrome P-450 CYP3A)
RN  - R60L0SM5BC (Midazolam)
SB  - IM
MH  - Biomarkers
MH  - *Cytochrome P-450 CYP3A/genetics
MH  - Cytochrome P-450 CYP3A Inducers
MH  - Drug Interactions
MH  - Humans
MH  - *Midazolam/pharmacokinetics
MH  - Models, Biological
PMC - PMC9468555
COIS- All authors are present or past employees and shareholders of Pfizer Inc.
EDAT- 2022/06/23 06:00
MHDA- 2022/09/15 06:00
PMCR- 2022/09/01
CRDT- 2022/06/22 02:43
PHST- 2022/05/24 00:00 [revised]
PHST- 2021/09/27 00:00 [received]
PHST- 2022/05/29 00:00 [accepted]
PHST- 2022/06/23 06:00 [pubmed]
PHST- 2022/09/15 06:00 [medline]
PHST- 2022/06/22 02:43 [entrez]
PHST- 2022/09/01 00:00 [pmc-release]
AID - CTS13352 [pii]
AID - 10.1111/cts.13352 [doi]
PST - ppublish
SO  - Clin Transl Sci. 2022 Sep;15(9):2184-2194. doi: 10.1111/cts.13352. Epub 2022 Jul 
      2.