A pharmacokinetic drug–drug interaction study between rosuvastatin and emvododstat, a potent anti‐SARS‐CoV‐2 (COVID‐19) DHODH (dihydroorotate dehydrogenase) inhibitor
Abstract 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 immunomod...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Wiley
2023-04-01
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| Series: | Pharmacology Research & Perspectives |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/prp2.1076 |
| _version_ | 1827969550598012928 |
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| author | Terri L. Morton Oscar L. Laskin Diksha Kaushik Lucy Lee Jiyuan Ma Allan Kristensen Kylie O'Keefe Lee Golden Matthew Klein Ronald Kong |
| author_facet | Terri L. Morton Oscar L. Laskin Diksha Kaushik Lucy Lee Jiyuan Ma Allan Kristensen Kylie O'Keefe Lee Golden Matthew Klein Ronald Kong |
| author_sort | Terri L. Morton |
| collection | DOAJ |
| description | Abstract 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 (Cmax) 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 Cmax 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. |
| first_indexed | 2024-04-09T18:39:27Z |
| format | Article |
| id | doaj.art-39ad2230eba34f49a3e6b8a52a05b53b |
| institution | Directory Open Access Journal |
| issn | 2052-1707 |
| language | English |
| last_indexed | 2024-04-09T18:39:27Z |
| publishDate | 2023-04-01 |
| publisher | Wiley |
| record_format | Article |
| series | Pharmacology Research & Perspectives |
| spelling | doaj.art-39ad2230eba34f49a3e6b8a52a05b53b2023-04-11T06:38:37ZengWileyPharmacology Research & Perspectives2052-17072023-04-01112n/an/a10.1002/prp2.1076A pharmacokinetic drug–drug interaction study between rosuvastatin and emvododstat, a potent anti‐SARS‐CoV‐2 (COVID‐19) DHODH (dihydroorotate dehydrogenase) inhibitorTerri L. Morton0Oscar L. Laskin1Diksha Kaushik2Lucy Lee3Jiyuan Ma4Allan Kristensen5Kylie O'Keefe6Lee Golden7Matthew Klein8Ronald Kong9PTC Therapeutics South Plainfield New Jersey USAPTC Therapeutics South Plainfield New Jersey USAPTC Therapeutics South Plainfield New Jersey USAPTC Therapeutics South Plainfield New Jersey USAPTC Therapeutics South Plainfield New Jersey USAPTC Therapeutics South Plainfield New Jersey USAPTC Therapeutics South Plainfield New Jersey USAPTC Therapeutics South Plainfield New Jersey USAPTC Therapeutics South Plainfield New Jersey USAPTC Therapeutics South Plainfield New Jersey USAAbstract 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 (Cmax) 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 Cmax 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.https://doi.org/10.1002/prp2.1076BCRPcoronavirusCOVID‐19DHODHpharmacokineticsPTC299 |
| spellingShingle | Terri L. Morton Oscar L. Laskin Diksha Kaushik Lucy Lee Jiyuan Ma Allan Kristensen Kylie O'Keefe Lee Golden Matthew Klein Ronald Kong A pharmacokinetic drug–drug interaction study between rosuvastatin and emvododstat, a potent anti‐SARS‐CoV‐2 (COVID‐19) DHODH (dihydroorotate dehydrogenase) inhibitor Pharmacology Research & Perspectives BCRP coronavirus COVID‐19 DHODH pharmacokinetics PTC299 |
| title | A pharmacokinetic drug–drug interaction study between rosuvastatin and emvododstat, a potent anti‐SARS‐CoV‐2 (COVID‐19) DHODH (dihydroorotate dehydrogenase) inhibitor |
| title_full | A pharmacokinetic drug–drug interaction study between rosuvastatin and emvododstat, a potent anti‐SARS‐CoV‐2 (COVID‐19) DHODH (dihydroorotate dehydrogenase) inhibitor |
| title_fullStr | A pharmacokinetic drug–drug interaction study between rosuvastatin and emvododstat, a potent anti‐SARS‐CoV‐2 (COVID‐19) DHODH (dihydroorotate dehydrogenase) inhibitor |
| title_full_unstemmed | A pharmacokinetic drug–drug interaction study between rosuvastatin and emvododstat, a potent anti‐SARS‐CoV‐2 (COVID‐19) DHODH (dihydroorotate dehydrogenase) inhibitor |
| title_short | A pharmacokinetic drug–drug interaction study between rosuvastatin and emvododstat, a potent anti‐SARS‐CoV‐2 (COVID‐19) DHODH (dihydroorotate dehydrogenase) inhibitor |
| title_sort | pharmacokinetic drug drug interaction study between rosuvastatin and emvododstat a potent anti sars cov 2 covid 19 dhodh dihydroorotate dehydrogenase inhibitor |
| topic | BCRP coronavirus COVID‐19 DHODH pharmacokinetics PTC299 |
| url | https://doi.org/10.1002/prp2.1076 |
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