Drugs in COVID-19 Clinical Trials: Predicting Transporter-Mediated Drug-Drug Interactions Using In Vitro Assays and Real-World Data.
Antiviral Agents
/ pharmacokinetics
COVID-19
/ virology
Clinical Trials as Topic
Drug Interactions
Drug Monitoring
/ methods
Drug-Related Side Effects and Adverse Reactions
/ etiology
Electronic Health Records
/ statistics & numerical data
HEK293 Cells
Humans
Hydroxychloroquine
/ pharmacokinetics
Membrane Transport Proteins
/ metabolism
Risk Assessment
/ methods
SARS-CoV-2
/ drug effects
Virus Internalization
/ drug effects
Virus Replication
/ drug effects
COVID-19 Drug Treatment
Journal
Clinical pharmacology and therapeutics
ISSN: 1532-6535
Titre abrégé: Clin Pharmacol Ther
Pays: United States
ID NLM: 0372741
Informations de publication
Date de publication:
07 2021
07 2021
Historique:
received:
15
12
2020
accepted:
14
03
2021
pubmed:
25
3
2021
medline:
29
6
2021
entrez:
24
3
2021
Statut:
ppublish
Résumé
Numerous drugs are currently under accelerated clinical investigation for the treatment of coronavirus disease 2019 (COVID-19); however, well-established safety and efficacy data for these drugs are limited. The goal of this study was to predict the potential of 25 small molecule drugs in clinical trials for COVID-19 to cause clinically relevant drug-drug interactions (DDIs), which could lead to potential adverse drug reactions (ADRs) with the use of concomitant medications. We focused on 11 transporters, which are targets for DDIs. In vitro potency studies in membrane vesicles or HEK293 cells expressing the transporters coupled with DDI risk assessment methods revealed that 20 of the 25 drugs met the criteria from regulatory authorities to trigger consideration of a DDI clinical trial. Analyses of real-world data from electronic health records, including a database representing nearly 120,000 patients with COVID-19, were consistent with several of the drugs causing transporter-mediated DDIs (e.g., sildenafil, chloroquine, and hydroxychloroquine). This study suggests that patients with COVID-19, who are often older and on various concomitant medications, should be carefully monitored for ADRs. Future clinical studies are needed to determine whether the drugs that are predicted to inhibit transporters at clinically relevant concentrations, actually result in DDIs.
Identifiants
pubmed: 33759449
doi: 10.1002/cpt.2236
pmc: PMC8217266
mid: NIHMS1702083
doi:
Substances chimiques
Antiviral Agents
0
Membrane Transport Proteins
0
Hydroxychloroquine
4QWG6N8QKH
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
108-122Subventions
Organisme : FDA HHS
ID : U01 FD005978
Pays : United States
Organisme : US Food and Drug Administration (FDA)
ID : U01FD004979/U01FD005978
Organisme : NIGMS NIH HHS
ID : R01 GM117163
Pays : United States
Organisme : UCSF-Stanford Center of Excellence in Regulatory Sciences and Innovation
Organisme : FDA HHS
ID : U01 FD004979
Pays : United States
Organisme : NIGMS NIH HHS
ID : T32 GM007175
Pays : United States
Informations de copyright
© 2021 The Authors. Clinical Pharmacology & Therapeutics © 2021 American Society for Clinical Pharmacology and Therapeutics.
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