Validation of a Drug Transporter Probe Cocktail Using the Prototypical Inhibitors Rifampin, Probenecid, Verapamil, and Cimetidine.
Journal
Clinical pharmacokinetics
ISSN: 1179-1926
Titre abrégé: Clin Pharmacokinet
Pays: Switzerland
ID NLM: 7606849
Informations de publication
Date de publication:
12 2020
12 2020
Historique:
pubmed:
7
6
2020
medline:
22
9
2021
entrez:
7
6
2020
Statut:
ppublish
Résumé
A novel cocktail containing four substrates of key drug transporters was previously optimized to eliminate mutual drug-drug interactions between the probes digoxin (P-glycoprotein substrate), furosemide (organic anion transporter 1/3), metformin (organic cation transporter 2, multidrug and toxin extrusion protein 1/2-K), and rosuvastatin (organic anion transporting polypeptide 1B1/3, breast cancer resistance protein). This clinical trial investigated the effects of four commonly employed drug transporter inhibitors on cocktail drug pharmacokinetics. In a randomized open-label crossover trial in 45 healthy male subjects, treatment groups received the cocktail with or without single oral doses of rifampin, verapamil, cimetidine or probenecid. Concentrations of the probe drugs in serial plasma samples and urine fractions were measured by validated liquid chromatography-tandem mass spectrometry assays to assess systemic exposure. The results were generally in accordance with known in vitro and/or clinical drug-drug interaction data. Single-dose rifampin increased rosuvastatin area under the plasma concentration-time curve up to the last quantifiable concentration (AUC Taking all the interaction results together, the transporter cocktail is considered to be validated as a sensitive and specific tool for evaluating transporter-mediated drug-drug interactions in drug development. EudraCT number 2017-001549-29.
Sections du résumé
BACKGROUND AND OBJECTIVE
A novel cocktail containing four substrates of key drug transporters was previously optimized to eliminate mutual drug-drug interactions between the probes digoxin (P-glycoprotein substrate), furosemide (organic anion transporter 1/3), metformin (organic cation transporter 2, multidrug and toxin extrusion protein 1/2-K), and rosuvastatin (organic anion transporting polypeptide 1B1/3, breast cancer resistance protein). This clinical trial investigated the effects of four commonly employed drug transporter inhibitors on cocktail drug pharmacokinetics.
METHODS
In a randomized open-label crossover trial in 45 healthy male subjects, treatment groups received the cocktail with or without single oral doses of rifampin, verapamil, cimetidine or probenecid. Concentrations of the probe drugs in serial plasma samples and urine fractions were measured by validated liquid chromatography-tandem mass spectrometry assays to assess systemic exposure.
RESULTS
The results were generally in accordance with known in vitro and/or clinical drug-drug interaction data. Single-dose rifampin increased rosuvastatin area under the plasma concentration-time curve up to the last quantifiable concentration (AUC
CONCLUSIONS
Taking all the interaction results together, the transporter cocktail is considered to be validated as a sensitive and specific tool for evaluating transporter-mediated drug-drug interactions in drug development.
CLINICAL TRIAL REGISTRATION
EudraCT number 2017-001549-29.
Identifiants
pubmed: 32504272
doi: 10.1007/s40262-020-00907-w
pii: 10.1007/s40262-020-00907-w
pmc: PMC7716890
doi:
Substances chimiques
Cimetidine
80061L1WGD
Verapamil
CJ0O37KU29
Probenecid
PO572Z7917
Rifampin
VJT6J7R4TR
Banques de données
EudraCT
['EudraCT 2017-001549-29']
Types de publication
Journal Article
Randomized Controlled Trial
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
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