Darunavir: Pharmacokinetics and drug interactions

Department of Pharmacology and Therapeutics, University of Liverpool, Liverpool, UK.
Antiviral therapy (Impact Factor: 3.02). 02/2008; 13(1):1-13.
Source: PubMed


Darunavir (TMC114) is a new HIV protease inhibitor that has demonstrated substantial antiretroviral activity against wild-type HIV-1 virus and multidrug-resistant strains. Darunavir inhibits and is primarily metabolized by cytochrome P450 3A (CYP3A) isoenzymes and is coadministered with low-dose ritonavir (darunavir/r); ritonavir is an inhibitor of CYP3A isoenzymes and pharmacologically enhances darunavir, resulting in increased plasma concentrations and allowing for a lower daily dose. The t1/2 (terminal elimination half-life) of darunavir is 15 h in the presence of ritonavir. An extensive darunavir/r drug-drug interaction programme has been undertaken, covering a wide range of therapeutic areas. Studies conducted in HIV-negative healthy volunteers and in HIV-infected patients show that the potential for interactions is well characterized and the interactions are manageable. For most drugs investigated, no dose adjustments of darunavir/r or the co-administered drug are required. This article reviews all the pharmacokinetic and drug-drug interaction studies conducted to date for darunavir/r, providing guidance on how to co-administer darunavir/r with many other antiretroviral or non-antiretroviral medications commonly used in HIV-infected individuals.

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    • "Figure 1 shows that (as expected) we observe a time-dependent increase in the appearance of HIV-1 pol DNA indicative of cell-cell spread within the control sample that was incubated in the absence of PI (Figure 1A and B). Notably, cell-to-cell spread of HIV-1 was potently blocked in the presence of both Lopinavir and Darunavir at doses corresponding to the maximum plasma concentrations (Cmax) (14 μM LPV; 12 μM DRV) achieved in vivo[35-37], with no increase in HIV-1 DNA detected during co-culture in the presence of drug (Figure 1A and B). Inhibiting de novo synthesis of reverse transcripts by blocking cell-to-cell spread would also be expected to impact on the appearance of 2-LTR circles that are used as a marker of HIV-1 nuclear import a step that immediately precedes proviral integration [38]. "
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