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. DOI: 10.1111/j.1365-2125.1997.tb00128.x
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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    ABSTRACT: The Human Immunodeficiency Virus type-1 (HIV-1) spreads by cell-free diffusion and by direct cell-to-cell transfer, the latter being a significantly more efficient mode of transmission. Recently it has been suggested that cell-to-cell spread may permit ongoing virus replication in the presence of antiretroviral therapy (ART) based on studies performed using Reverse Transcriptase Inhibitors (RTIs). Protease Inhibitors (PIs) constitute an important component of ART; however whether this class of inhibitors can suppress cell-to-cell transfer of HIV-1 is unexplored. Here we have evaluated the inhibitory effect of PIs during cell-to-cell spread of HIV-1 between T lymphocytes. Using quantitative assays in cell line and primary cell systems that directly measure the early steps of HIV-1 infection we find that the PIs Lopinavir and Darunavir are equally potent against both cell-free and cell-to-cell spread of HIV-1. We further show that a protease resistant mutant maintains its resistant phenotype during cell-to-cell spread is transmitted more efficiently than wild-type virus in the presence of drug. By contrast we find that T cell-T cell spread of HIV-1 is 4-20 fold more resistant to inhibition by the RTIs Nevirapine, Zidovudine and Tenofovir. Notably, varying the ratio of infected and uninfected cells in co-culture impacted on the degree of inhibition, indicating that the relative efficacy of ART is dependent on the multiplicity of infection. We conclude that if the variable effects of antiviral drugs on cell-to-cell virus dissemination of HIV-1 do indeed impact on viral replication and maintenance of viral reservoirs this is likely to be influenced by the antiviral drug class, since PIs appear particularly effective against both modes of HIV-1 spread.
    Full-text · Article · Dec 2013 · Retrovirology
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    • "As an important component of the HAART, darunavir (Figure 1), a synthetic nonpeptidic protease inhibitor developed by the pharmaceutical company Tibotec in 1998 [3], has demonstrated high efficacy against HIV [4] [5]. This compound was licensed in June 2006 in the United States and in February 2007 in the European Union [1]. "
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    ABSTRACT: Chemical and physical degradation of drugs may result in altered therapeutic efficacy and even toxic effects. Therefore, the aim of this work was to study the stability of darunavir and to develop and validate a liquid chromatography (LC) method to determine darunavir in raw material and tablets in the presence of degradation products. The novel method showed to be linear from 6.0 to 21.0 μg/mL, with high precision (CV < 2%) and accuracy (recuperation of 99.64%). It is simple and reliable, free of placebo interferences. The robustness of the method was evaluated by a factorial design using seven different parameters. Forced degradation study was done under alkaline, acidic, and oxidative stress at ambient temperature and by heating. The LC method was able to quantify and separate darunavir and its degradation products. Darunavir showed to be unstable under alkaline, acid, and oxidative conditions. The novelty of this study is understanding the factors that affect darunavir ethanolate stability in tablets, which is the first step to unravel the path to know the degradation products. The novel stability-indicating method can be used to monitor the drug and the main degradation products in low concentrations in which there is linearity.
    Full-text · Article · May 2013
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    ABSTRACT: Darunavir is the result of wide and in-depth investigation into HIV protease inhibitors (PIs). This drug is a non-peptide PI, with a distinct chemical structure that, by conferring it drug with enhanced binding affinity and a slower dissociation rate, makes it more potent than the remaining PIs developed to date. Because of its pharmacokinetic characteristics, darunavir must be coadministered with low doses of ritonavir. Furthermore, these characteristics allow oral administration (preferably with meals), once-daily administration in non-resistant HIV strains, and a less complicated treatment regimen with improved convenience in highly varied contexts, including mild-to-moderate renal and hepatic impairment. The potential of darunavir for pharmacological interactions is highly acceptable and this drug can be administered without dose adjustments with almost all antiretroviral agents except maraviroc, lopinavir, saquinavir and tipranavir. There are no problems of pharmacodynamic antagonism with any of these drugs. Cytotoxic doses are well above therapeutic doses, providing a wide safety margin. The spectrum of action is very wide, and darunavir is effective against all subtypes of HIV-1 and against HIV-2 and acts well in mononuclear and monocyte/macrophage cell lines. Darunavir is also active against most HIV strains resistant to the remaining PIs and the robustness of this drug against the known mechanisms of resistance of HIV is also superior to that of the other available PIs. Consequently, the induction and selection of mutations conferring resistance to this drug may be slower and more difficult, resulting in its antiviral effect remaining unchanged for prolonged periods.
    No preview · Article · Oct 2008 · Enfermedades Infecciosas y Microbiología Clínica
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