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Original article

The effects of a nucleoside-sparing antiretroviral regimen on the pharmacokinetics of ritonavir-boosted darunavir in HIV type-1-infected patients

Lucy Garvey, Ngaire Latch, Otto W Erlwein, Nicola E Mackie, John Walsh, George Scullard, Myra O McClure, Laura Dickinson, David Back, Alan Winston

Corresponding author name: Lucy Garvey
Corresponding author e-mail: l.garvey@imperial.ac.uk

Citation: Antiviral Therapy 2010; 15:213-218
doi: 10.3851/IMP1517

Date accepted: 09 October 2009
Date published online: 01 April 2010

Abstract

Background: Nucleoside-sparing combination antiretroviral therapy (cART) regimens might be an attractive therapeutic option for HIV type-1 (HIV-1)-infected patients; however, the pharmacokinetic profiles of such regimens are frequently unknown.

Methods: Fourteen HIV-1-infected patients (age 21–55 years, 64% male) on stable cART with plasma HIV RNA <50 copies/ml entered this Phase I pharmacokinetic study. In period 1, patients received tenofovir/emtricitabine/-darunavir/ritonavir (300/200/800/100 mg) all once daily. During period 2, raltegravir 400 mg twice daily was added to the regimen and in period 3 tenofovir/emtricitabine was discontinued. At steady state, intensive pharmacokinetic sampling was undertaken. Differences in the geometric mean ratio (GMR) for pharmacokinetic parameters between periods 2 versus 1 and period 3 versus 1 were assessed for darunavir and ritonavir (period 3 versus 2 for raltegravir).

Results: No statistically significant differences in pharmacokinetic parameters were observed between period 2 versus period 1. During period 3, darunavir GMR (95% confidence interval) values for trough and maximum plasma concentration (Ctrough and Cmax), area under the plasma concentration–time curve (AUC) and elimination half-life (t1/2) were 0.64 ng/ml (0.44–0.93), 1.05 ng/ml (0.90–1.24), 0.92 ng h/ml (0.78–1.08) and 0.69 h (0.46–1.05), respectively, when compared with period 1. No statistically significant changes were observed in ritonavir or raltegravir pharmacokinetic parameters. Darunavir Ctrough<550 ng/ml (the minimum effective concentration for protease-resistant HIV viral isolates) was observed in four patients during period 3 only. No clinically significant safety concerns were reported.

Conclusions: Darunavir Ctrough is reduced by 36% when administered without tenofovir/emtricitabine in HIV-1-infected patients. This interaction might be of clinical significance in the management of individuals with protease-resistant HIV viral isolates.

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