Therapeutic amprenavir concentrations in cerebrospinal fluid.

Department of Neurosciences, University of California, San Diego, San Diego, California, USA.
Antimicrobial Agents and Chemotherapy (Impact Factor: 4.57). 01/2012; 56(4):1985-9. DOI: 10.1128/AAC.05098-11
Source: PubMed

ABSTRACT Antiretrovirals that reach higher concentrations in cerebrospinal fluid (CSF) are associated with better control of HIV in CSF and possibly better neurocognitive performance. The objective of this study was to determine whether amprenavir (APV) concentrations in CSF are in the therapeutic range. Individuals were selected based on the use of regimens that included fosamprenavir (FPV), a prodrug of APV, and the availability of stored CSF and matched plasma. Total APV was measured in 119 matched CSF-plasma pairs from 75 subjects by high-performance liquid chromatography (HPLC) (plasma) or liquid chromatography tandem mass spectrometry (LC/MS/MS) (CSF). Concentrations were compared to the 50% inhibitory concentration (IC₅₀) for wild-type HIV (5.6 ng/ml). Subjects were predominantly middle-aged (median 44 years) white (57%) men (78%) with AIDS (77%). APV was detected in all but 4 CSF specimens, with a median concentration of 24.8 ng/ml (interquartile range [IQR], 16.2 to 44.0). The median CSF-to-plasma ratio was 0.012 (IQR, 0.008 to 0.018). CSF concentrations correlated with plasma concentrations (rho = 0.61; P < 0.0001) and with postdose sampling interval (rho = -0.29; P = 0.0019). APV concentrations in CSF exceeded the median IC₅₀ for wild-type HIV in more than 97% of CSF specimens with detectable APV by a median of 4.4-fold (IQR, 2.9 to 7.9). We conclude that administration of fosamprenavir should contribute to control of HIV replication in the central nervous system (CNS) as a component of effective antiretroviral regimens.

  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The prevalence of HIV-associated neurocognitive impairment in perinatally HIV-infected children has declined since the introduction of combination antiretroviral therapy (cART). Early initiation of cART in infancy has been shown to positively impact neurodevelopment; however, children continue to be diagnosed with HIV outside of the early infancy period and can experience subtle to severe neurocognitive deficits despite cART. The causes of these neurocognitive deficits despite effective cART are multifactorial and likely include continued viral replication in the CNS, ongoing neuroinflammation, irreversible CNS injury prior to cART initiation, neurotoxic effects of cART, and socioeconomic and psychosocial effects. Many aspects of our understanding of HIV-associated neurocognitive disorders have emerged from research in adult patients, but perinatally HIV-infected children represent a very different population. These children were exposed to HIV during a period of rapid brain development and have lifelong infection and potential lifelong cART exposure. HIV is no longer a rapidly fatal disease, and most HIV-infected children in resource-rich countries are living into adulthood. It is therefore critical to optimize neurocognitive outcomes of these youth. This review summarizes current understanding of the pathogenesis of HIV-associated CNS infection and the impact of cART on neurocognitive function in children and adolescents and discusses important areas for future research. Copyright © 2014 John Wiley & Sons, Ltd.
    Reviews in Medical Virology 05/2014; · 7.62 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Antiretroviral drug therapy plays a cornerstone role in the treatment of human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome patients. Despite obvious advances over the past 3 decades, new approaches toward improved management of infected individuals are still required. Drug distribution to the central nervous system (CNS) is required in order to limit and control viral infection, but the presence of natural barrier structures, in particular the blood-brain barrier, strongly limits the perfusion of anti-HIV compounds into this anatomical site. Nanotechnology-based approaches may help providing solutions for antiretroviral drug delivery to the CNS by potentially prolonging systemic drug circulation, increasing the crossing and reducing the efflux of active compounds at the blood-brain barrier, and providing cell/tissue-targeting and intracellular drug delivery. After an initial overview on the basic features of HIV infection of the CNS and barriers to active compound delivery to this anatomical site, this review focuses on recent strategies based on antiretroviral drug-loaded solid nanoparticles and drug nanosuspensions for the potential management of HIV infection of the CNS.
    International Journal of Nanomedicine 01/2014; 9:1757-1769. · 3.46 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The membrane-associated drug transporter, P-glycoprotein (P-gp), plays an essential role in drug efflux from the brain. Induction of this protein at the blood-brain barrier (BBB) could further affect drug permeability into the brain. At present, P-gp induction at the BBB mediated by antiretroviral drugs has not been fully investigated. Since P-gp expression is regulated by ligand-activated nuclear receptors i.e., human Pregnane X Receptor (hPXR) and human Constitutive Androstane Receptor (hCAR), these receptors could represent potential pathways involved in P-gp induction by antiretroviral drugs. The aims of this study were: i) to determine whether antiretroviral drugs currently used in HIV pharmacotherapy are ligands for hPXR or hCAR and ii) to examine P-gp function and expression in human brain microvessel endothelial cells treated with antiretroviral drugs identified as ligands of hPXR and/or hCAR. Luciferase reporter gene assays were performed to examine the activation of hPXR and hCAR by antiretroviral drugs. The hCMEC/D3 cell line, known to display several morphological and biochemical properties of the BBB in humans, was utilized to examine P-gp induction following 72 h exposure to these agents. Amprenavir, atazanavir, darunavir, efavirenz, ritonavir and lopinavir were found to activate hPXR, whereas, abacavir, efavirenz and nevirapine were found to activate hCAR. P-gp expression and function were significantly induced in hCMEC/D3 cells treated with these drugs at clinical plasma concentrations. Together, our data suggest that P-gp induction could occur at the BBB during chronic treatment with antiretroviral drugs identified to be ligands of hPXR and/or hCAR.
    Antimicrobial Agents and Chemotherapy 07/2013; · 4.57 Impact Factor

Full-text (2 Sources)

Available from
May 27, 2014