The Effect of CYP3A Induction and Inhibition on the Pharmacokinetics of Laquinimod, a Novel Neuroimmunomodulator.
Adult
Area Under Curve
Biological Availability
Cross-Over Studies
Cytochrome P-450 CYP3A
/ metabolism
Cytochrome P-450 CYP3A Inducers
/ administration & dosage
Cytochrome P-450 CYP3A Inhibitors
/ administration & dosage
Dose-Response Relationship, Drug
Drug Administration Schedule
Drug Interactions
Drug Therapy, Combination
/ adverse effects
Female
Healthy Volunteers
Humans
Male
Middle Aged
Neuroimmunomodulation
/ drug effects
Quinolones
/ administration & dosage
Safety
CYP3A4
drug-drug Interaction
laquinimod
Journal
Clinical pharmacology in drug development
ISSN: 2160-7648
Titre abrégé: Clin Pharmacol Drug Dev
Pays: United States
ID NLM: 101572899
Informations de publication
Date de publication:
11 2020
11 2020
Historique:
received:
12
12
2019
accepted:
02
02
2020
pubmed:
3
4
2020
medline:
28
9
2021
entrez:
3
4
2020
Statut:
ppublish
Résumé
Laquinimod, a neuroimmunomodulator, is extensively metabolized by cytochrome P450 (CYP) 3A4, and modulations of CYP3A4 activity may lead to alterations in the pharmacokinetics and/or clinical effects of laquinimod. To determine the drug-drug interaction potential of laquinimod with CYP3A inhibitors and inducers, interaction assessments were conducted in healthy volunteers using single-dose administration of laquinimod before and after multiple dosing of CYP3A inhibitors (ketoconazole, fluconazole, and cimetidine) or a CYP3A4 inducer (rifampin). For ketoconazole, subjects (n = 14) received laquinimod 0.6 mg following 1 day of ketoconazole (400 mg daily) pretreatment, a single concomitant dose, and 28 additional days. For fluconazole, subjects (n = 14) received laquinimod 0.6 mg after a single fluconazole dose of 400 mg followed by 200-mg daily fluconazole administration for 20 additional days. For cimetidine, subjects (n = 14) received laquinimod 0.6 mg following 1 day of cimetidine (800 mg twice daily) pretreatment, a single concomitant dose, and 21 additional days. For rifampin, subjects (n = 14) received laquinimod 0.6 mg following 9 days of rifampin (600 mg daily) pretreatment, a single concomitant dose, and 12 additional days. Coadministration of laquinimod with CYP3A inhibitors, ketoconazole, fluconazole, and cimetidine increased laquinimod area under the plasma concentration-time curve from time zero to infinity by approximately 3.1-, 2.5-, and 1.1-fold, respectively. Coadministration of laquinimod with rifampin decreased laquinimod area under the plasma concentration-time curve from time zero to infinity by 5-fold. These results indicate that coadministration of laquinimod with moderate to strong inhibitors of CYP3A or strong inducers of CYP3A may give rise to significant pharmacokinetic drug interactions.
Substances chimiques
Cytochrome P-450 CYP3A Inducers
0
Cytochrome P-450 CYP3A Inhibitors
0
Quinolones
0
laquinimod
908SY76S4G
Cytochrome P-450 CYP3A
EC 1.14.14.1
Types de publication
Comparative Study
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1015-1024Informations de copyright
© 2020, The American College of Clinical Pharmacology.
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