Population pharmacokinetics of dolutegravir: influence of drug-drug interactions in a real-life setting.

Détails

ID Serval
serval:BIB_525CE7DE74FD
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Titre
Population pharmacokinetics of dolutegravir: influence of drug-drug interactions in a real-life setting.
Périodique
The Journal of antimicrobial chemotherapy
Auteur(s)
Barcelo C., Aouri M., Courlet P., Guidi M., Braun D.L., Günthard H.F., Piso R.J., Cavassini M., Buclin T., Decosterd L.A., Csajka C.
Collaborateur(s)
Swiss HIV Cohort Study
Contributeur(s)
Anagnostopoulos A., Battegay M., Bernasconi E., Böni J., Braun D.L., Bucher H.C., Calmy A., Cavassini M., Ciuffi A., Dollenmaier G., Egger M., Elzi L., Fehr J., Fellay J., Furrer H., Fux C.A., Günthard H.F., Haerry D., Hasse B., Hirsch H.H., Hoffmann M., Hösli I., Huber M., Kahlert C.R., Kaiser L., Keiser O., Klimkait T., Kouyos R.D., Kovari H., Ledergerber B., Martinetti G., Martinez de Tejada B., Marzolini C., Metzner K.J., Müller N., Nicca D., Paioni P., Pantaleo G., Perreau M., Rauch A., Rudin C., Scherrer A.U., Schmid P., Speck R., Stöckle M., Tarr P., Trkola A., Vernazza P., Wandeler G., Weber R., Yerly S.
ISSN
1460-2091 (Electronic)
ISSN-L
0305-7453
Statut éditorial
Publié
Date de publication
01/09/2019
Peer-reviewed
Oui
Volume
74
Numéro
9
Pages
2690-2697
Langue
anglais
Notes
Publication types: Journal Article
Publication Status: ppublish
Résumé
Dolutegravir is widely prescribed owing to its potent antiviral activity, high genetic barrier and good tolerability. The aim of this study was to characterize dolutegravir's pharmacokinetic profile and variability in a real-life setting and to identify individual factors and co-medications affecting dolutegravir disposition.
A population pharmacokinetic model was developed using NONMEM®. Relevant demographic factors, clinical factors and co-medications were tested as potential covariates. Simulations based on the final model served to compare expected dolutegravir concentrations under standard and alternative dosage regimens in the case of drug-drug interactions.
A total of 620 dolutegravir plasma concentrations were collected from 521 HIV-infected individuals under steady-state conditions. A one-compartment model with first-order absorption and elimination best characterized dolutegravir pharmacokinetics. Typical dolutegravir apparent clearance (CL/F) was 0.93 L/h with 32% between-subject variability, the apparent volume of distribution was 20.2 L and the absorption rate constant was fixed to 2.24 h-1. Older age, higher body weight and current smoking were associated with higher CL/F. Atazanavir co-administration decreased dolutegravir CL/F by 38%, while darunavir modestly increased CL/F by 14%. Rifampicin co-administration showed the largest impact on CL/F. Simulations suggest that average dolutegravir trough concentrations are 63% lower after 50 mg/12h with rifampicin compared with a standard dosage of 50 mg/24h without rifampicin. Average trough concentrations after 100 mg/24h and 100 mg/12h with rifampicin are 92% and 25% lower than the standard dosage without rifampicin, respectively.
Patients co-treated with dolutegravir and rifampicin might benefit from therapeutic drug monitoring and individualized dosage increase, up to 100 mg/12 h in some cases.
Pubmed
Web of science
Open Access
Oui
Création de la notice
14/06/2019 17:18
Dernière modification de la notice
23/10/2019 5:13
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