Titre
Cell disposition of raltegravir and newer antiretrovirals in HIV-infected patients: high inter-individual variability in raltegravir cellular penetration.
Type
article
Institution
UNIL/CHUV/Unisanté + institutions partenaires
Périodique
Auteur(s)
Fayet Mello, A.
Auteure/Auteur
Buclin, T.
Auteure/Auteur
Franc, C.
Auteure/Auteur
Colombo, S.
Auteure/Auteur
Cruchon, S.
Auteure/Auteur
Guignard, N.
Auteure/Auteur
Biollaz, J.
Auteure/Auteur
Telenti, A.
Auteure/Auteur
Decosterd, L.A.
Auteure/Auteur
Cavassini, M.
Auteure/Auteur
Liens vers les personnes
ISSN
1460-2091
Statut éditorial
Publié
Date de publication
2011
Volume
66
Numéro
7
Première page
1573
Dernière page/numéro d’article
1581
Langue
anglais
Résumé
Objectives The site of pharmacological activity of raltegravir is intracellular. Our aim was to determine the extent of raltegravir cellular penetration and whether raltegravir total plasma concentration (C(tot)) predicts cellular concentration (C(cell)). Methods Open-label, prospective, pharmacokinetic study on HIV-infected patients on a stable raltegravir-containing regimen. Plasma and peripheral blood mononuclear cells were simultaneously collected during a 12 h dosing interval after drug intake. C(tot) and C(cell) of raltegravir, darunavir, etravirine, maraviroc and ritonavir were measured by liquid chromatography coupled to tandem mass spectrometry after protein precipitation. Longitudinal mixed effects analysis was applied to the C(cell)/C(tot) ratio. Results Ten HIV-infected patients were included. The geometric mean (GM) raltegravir total plasma maximum concentration (C(max)), minimum concentration (C(min)) and area under the time-concentration curve from 0-12 h (AUC(0-12)) were 1068 ng/mL, 51.1 ng/mL and 4171 ng·h/mL, respectively. GM raltegravir cellular C(max), C(min) and AUC(0-12) were 27.5 ng/mL, 2.9 ng/mL and 165 ng·h/mL, respectively. Raltegravir C(cell) corresponded to 5.3% of C(tot) measured simultaneously. Both concentrations fluctuate in parallel, with C(cell)/C(tot) ratios remaining fairly constant for each patient without a significant time-related trend over the dosing interval. The AUC(cell)/AUC(tot) GM ratios for raltegravir, darunavir and etravirine were 0.039, 0.14 and 1.55, respectively. Conclusions Raltegravir C(cell) correlated with C(tot) (r = 0.86). Raltegravir penetration into cells is low overall (∼5% of plasma levels), with distinct raltegravir cellular penetration varying by as much as 15-fold between patients. The importance of this finding in the context of development of resistance to integrase inhibitors needs to be further investigated.
PID Serval
serval:BIB_525AF0812F4D
PMID
Open Access
Oui
Date de création
2011-06-29T11:29:24.862Z
Date de création dans IRIS
2025-05-20T17:33:31Z
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Nom
REF.pdf
Version du manuscrit
published
Taille
320.55 KB
Format
Adobe PDF
PID Serval
serval:BIB_525AF0812F4D.P001
URN
urn:nbn:ch:serval-BIB_525AF0812F4D9
Somme de contrôle
(MD5):8ad56d40e7b8eda14121ec57d7787b99