Variations of CYP3A activity induced by antiretroviral treatment in HIV-1 infected patients.

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Serval ID
serval:BIB_7E60EAA242E4
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Variations of CYP3A activity induced by antiretroviral treatment in HIV-1 infected patients.
Journal
European journal of clinical pharmacology
Author(s)
Fellay J., Marzolini C., Decosterd L., Golay K.P., Baumann P., Buclin T., Telenti A., Eap C.B.
ISSN
0031-6970
Publication state
Published
Issued date
2005
Peer-reviewed
Oui
Volume
60
Number
12
Pages
865-73
Language
english
Notes
Publication types: Clinical Trial ; Journal Article ; Research Support, Non-U.S. Gov't - Publication Status: ppublish
Abstract
OBJECTIVE: To measure the in vivo variations of CYP3A activity induced by anti-HIV drugs in human immunodeficiency virus (HIV)1-positive patients. METHODS: A low oral dose of midazolam (MID) (0.075 mg) was given to the patients and the 30-min total 1-OH midazolam (1-OHMID)/MID ratio was determined. Patients were phenotyped either before the introduction of antiretroviral treatments (control group, 90 patients) or after a variable period of antiretroviral treatment (56 patients). Twenty-one subjects underwent multiple phenotyping tests (before and during the course of the treatment). RESULTS: The median MID ratio was 3.51 in the control group (range 0.20-14.6). It was 5-fold higher in the group with efavirenz (28 patients; median, range: 16.0, 3.81-367; P < 0.0001), 13-fold lower with nelfinavir (18 patients; 0.27, 0.06-36.3; P < 0.0001), 17-fold lower with efavirenz + ritonavir (three patients; 0.21, 0.05-0.47; P = 0.006), 50-fold lower with ritonavir (four patients; 0.07, 0.06-0.17; P = 0.0007), and 7-fold lower with nevirapine + (ritonavir or nelfinavir or grapefruit juice) (three patients; 0.48, 0.03-1.83; P = 0.03). CYP3A activity was lower in the efavirenz + ritonavir group (P = 0.01) and in the ritonavir group (P = 0.04) than in the nelfinavir group, although already strongly inhibited in the latter. CONCLUSION: The low-dose MID phenotyping test was successfully used to measure the in vivo variations of CYP3A activity induced by antiretroviral drugs. Efavirenz strongly induces CYP3A activity, while ritonavir almost completely inhibits it. Nelfinavir strongly decreases CYP3A activity, but to a lesser extent than ritonavir. The inhibition of CYP3A by ritonavir or nelfinavir offsets the inductive effects of efavirenz or nevirapine administered concomitantly. Finally, no induction of CYP3A activity was noticeable after long-term administration of ritonavir at low dosages (200 mg/day b.i.d.) or of nelfinavir at standard dosages (2,500 mg/day b.i.d.).
Keywords
Adult, Aged, Anti-HIV Agents, Aryl Hydrocarbon Hydroxylases, Cytochrome P-450 CYP3A, Drug Interactions, Drug Therapy, Combination, Enzyme Activation, Female, HIV Infections, Humans, Male, Midazolam, Middle Aged, Oxidoreductases, N-Demethylating, Phenotype
Pubmed
Web of science
Open Access
Yes
Create date
05/02/2008 14:40
Last modification date
01/10/2019 7:18
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