PMID- 36938928
OWN - NLM
STAT- MEDLINE
DCOM- 20230321
LR  - 20231106
IS  - 2052-1707 (Electronic)
IS  - 2052-1707 (Linking)
VI  - 11
IP  - 2
DP  - 2023 Apr
TI  - A pharmacokinetic drug-drug interaction study between rosuvastatin and 
      emvododstat, a potent anti-SARS-CoV-2 (COVID-19) DHODH (dihydroorotate 
      dehydrogenase) inhibitor.
PG  - e01076
LID - 10.1002/prp2.1076 [doi]
LID - e01076
AB  - A therapeutic agent that targets both viral replication and the hyper-reactive 
      immune response would offer a highly desirable treatment for severe acute 
      respiratory syndrome coronavirus 2 (SARS-CoV-2; COVID-19) management. Emvododstat 
      (PTC299) was found to be a potent inhibitor of immunomodulatory and 
      inflammation-related processes by the inhibition of dihydroorotate dehydrogenase 
      (DHODH) to reduce SARS-CoV-2 replication. DHODH is the rate-limiting enzyme of 
      the de novo pyrimidine nucleotide biosynthesis pathway. This drug interaction 
      study was performed to determine whether emvododstat was an inhibitor of breast 
      cancer resistance protein (BCRP) transporters in humans. Potential drug-drug 
      interactions (DDIs) between emvododstat and a BCRP transporter substrate 
      (rosuvastatin) were investigated by measuring plasma rosuvastatin concentrations 
      before and after emvododstat administration. There was no apparent difference in 
      rosuvastatin plasma exposure. The geometric means of maximum plasma rosuvastatin 
      concentrations (C(max) ) were 4369 (rosuvastatin) and 5141 pg/mL (rosuvastatin + 
      emvododstat) at 4 h postdose. Geometric mean rosuvastatin area under the 
      concentration-time curve (AUC) from time 0 to the last measurable plasma 
      concentration was 45 616 and 48 975 h.pg/mL when administered alone and after 
      7 days of b.i.d. emvododstat dosing, respectively. Geometric least squares mean 
      ratios for C(max) and AUC were approximately equal to 1. Overall, administration 
      of multiple doses of 100 mg emvododstat b.i.d. for 7 days in combination with a 
      single dose of rosuvastatin was safe and well tolerated. Emvododstat can be 
      safely administered with other BCRP substrate drugs. Hence, pharmacokinetic DDI 
      mediated via BCRP inhibition is not expected when emvododstat and BCRP substrates 
      are coadministered.
CI  - (c) 2023 PTC Therapeutics. Pharmacology Research & Perspectives published by 
      British Pharmacological Society and American Society for Pharmacology and 
      Experimental Therapeutics and John Wiley & Sons Ltd.
FAU - Morton, Terri L
AU  - Morton TL
AUID- ORCID: 0000-0002-5004-8761
AD  - PTC Therapeutics, South Plainfield, New Jersey, USA.
FAU - Laskin, Oscar L
AU  - Laskin OL
AD  - PTC Therapeutics, South Plainfield, New Jersey, USA.
FAU - Kaushik, Diksha
AU  - Kaushik D
AD  - PTC Therapeutics, South Plainfield, New Jersey, USA.
FAU - Lee, Lucy
AU  - Lee L
AD  - PTC Therapeutics, South Plainfield, New Jersey, USA.
FAU - Ma, Jiyuan
AU  - Ma J
AD  - PTC Therapeutics, South Plainfield, New Jersey, USA.
FAU - Kristensen, Allan
AU  - Kristensen A
AD  - PTC Therapeutics, South Plainfield, New Jersey, USA.
FAU - O'Keefe, Kylie
AU  - O'Keefe K
AD  - PTC Therapeutics, South Plainfield, New Jersey, USA.
FAU - Golden, Lee
AU  - Golden L
AD  - PTC Therapeutics, South Plainfield, New Jersey, USA.
FAU - Klein, Matthew
AU  - Klein M
AD  - PTC Therapeutics, South Plainfield, New Jersey, USA.
FAU - Kong, Ronald
AU  - Kong R
AUID- ORCID: 0000-0002-4692-7499
AD  - PTC Therapeutics, South Plainfield, New Jersey, USA.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Pharmacol Res Perspect
JT  - Pharmacology research & perspectives
JID - 101626369
RN  - 83MVU38M7Q (Rosuvastatin Calcium)
RN  - 053QD2I96A (emvododstat)
RN  - 0 (ATP Binding Cassette Transporter, Subfamily G, Member 2)
RN  - 0 (Dihydroorotate Dehydrogenase)
RN  - 0 (Pyrimidines)
RN  - 0 (Neoplasm Proteins)
RN  - 0 (Membrane Transport Proteins)
SB  - IM
MH  - Humans
MH  - Rosuvastatin Calcium/pharmacology/therapeutic use
MH  - ATP Binding Cassette Transporter, Subfamily G, Member 2
MH  - *Dihydroorotate Dehydrogenase
MH  - SARS-CoV-2
MH  - Pyrimidines
MH  - *COVID-19
MH  - Neoplasm Proteins/metabolism
MH  - Membrane Transport Proteins/metabolism
MH  - Drug Interactions
PMC - PMC10026081
OTO - NOTNLM
OT  - BCRP
OT  - COVID-19
OT  - DHODH
OT  - PTC299
OT  - SARS-CoV-2
OT  - coronavirus
OT  - pharmacokinetics
COIS- The authors have no conflicting interests.
EDAT- 2023/03/21 06:00
MHDA- 2023/03/22 06:00
PMCR- 2023/03/20
CRDT- 2023/03/20 05:54
PHST- 2022/12/08 00:00 [revised]
PHST- 2022/09/02 00:00 [received]
PHST- 2023/01/16 00:00 [accepted]
PHST- 2023/03/20 05:54 [entrez]
PHST- 2023/03/21 06:00 [pubmed]
PHST- 2023/03/22 06:00 [medline]
PHST- 2023/03/20 00:00 [pmc-release]
AID - PRP21076 [pii]
AID - 10.1002/prp2.1076 [doi]
PST - ppublish
SO  - Pharmacol Res Perspect. 2023 Apr;11(2):e01076. doi: 10.1002/prp2.1076.