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Pharmacokinetic modelling of darunavir/ritonavir dose reduction (800/100 to 400/100 mg once daily) in a darunavir/ritonavir-containing regimen in virologically suppressed HIV-infected patients: ANRS 165 DARULIGHT sub-study.
- Source :
-
The Journal of antimicrobial chemotherapy [J Antimicrob Chemother] 2018 Aug 01; Vol. 73 (8), pp. 2120-2128. - Publication Year :
- 2018
-
Abstract
- Background: In the ANRS 165 DARULIGHT study (NCT02384967) carried out in HIV-infected patients, the use of a darunavir/ritonavir-containing regimen with a switch to a reduced dose of darunavir maintained virological efficacy (≤50 copies/mL) for 48 weeks with a good safety profile.<br />Objectives: To assess the total and unbound blood plasma pharmacokinetics of darunavir and associated antiretrovirals, and their penetration into semen before and after dose reduction.<br />Patients and Methods: Patients receiving a darunavir/ritonavir (800/100 mg q24h)-containing regimen for >6 months with plasma HIV-RNA ≤50 copies/mL for >12 months were switched to 400/100 mg darunavir/ritonavir q24h at week 0. A 24 h intensive pharmacokinetic blood sampling and a trough seminal sampling were performed before (week 0) and after (week 12) dose reduction. Individual pharmacokinetic parameter estimates were obtained using non-linear mixed-effect modelling for darunavir/ritonavir in blood plasma and used to test for bioequivalence, whereas darunavir/ritonavir in seminal plasma and NRTIs were analysed using a non-compartmental approach.<br />Results and Conclusions: Fifteen patients completed the intensive pharmacokinetic analysis. There was no significant decrease in total and unbound darunavir blood plasma exposure despite a 50% decrease in darunavir daily dose from 800 to 400 mg (AUC0-24 = 65 563 versus 52 518 ng·h/mL; P = 0.25). A decrease in apparent oral clearance (CL/F) of both darunavir and ritonavir at week 12 suggests a modification of the initial darunavir/ritonavir daily dose balance (800/100 to 400/100 mg), in favour of a reduced inducer effect of darunavir on cytochrome P450 and efflux transporters compared with the standard dose.
- Subjects :
- Adult
Darunavir blood
Drug Therapy, Combination
HIV Protease Inhibitors administration & dosage
HIV Protease Inhibitors blood
HIV Protease Inhibitors pharmacokinetics
Humans
Male
Middle Aged
Plasma chemistry
Reverse Transcriptase Inhibitors blood
Reverse Transcriptase Inhibitors pharmacokinetics
Ritonavir blood
Semen chemistry
Therapeutic Equivalency
Darunavir administration & dosage
Darunavir pharmacokinetics
HIV Infections drug therapy
Ritonavir administration & dosage
Ritonavir pharmacokinetics
Subjects
Details
- Language :
- English
- ISSN :
- 1460-2091
- Volume :
- 73
- Issue :
- 8
- Database :
- MEDLINE
- Journal :
- The Journal of antimicrobial chemotherapy
- Publication Type :
- Academic Journal
- Accession number :
- 29905808
- Full Text :
- https://doi.org/10.1093/jac/dky193