Therapeutic amprenavir concentrations in cerebrospinal fluid.
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.
- SourceAvailable from: William J Muller[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
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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
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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
Therapeutic Amprenavir Concentrations in Cerebrospinal Fluid
David Croteau,aScott Letendre,bBrookie M. Best,c,eSteven S. Rossi,cRonald J. Ellis,aDavid B. Clifford,fAnn C. Collier,g
Benjamin B. Gelman,hChristina M. Marra,gJustin McArthur,iJ. Allen McCutchan,bSusan Morgello,jDavid M. Simpson,jLauren Way,d
Edmund Capparelli,cand Igor Grantdfor the CHARTER Group
Departments of Neurosciences,aMedicine,bPediatrics,cand Psychiatrydand Skaggs School of Pharmacy and Pharmaceutical Sciences,eUniversity of California, San Diego,
San Diego, California, USA; Washington University, St. Louis, Missouri, USAf; University of Washington, Seattle, Washington, USAg; University of Texas Medical Branch,
Galveston, Texas, USAh; Johns Hopkins University, Baltimore, Maryland, USAi; and Mount Sinai School of Medicine, New York, New York, USAj
spinal fluid (CSF) of untreated individuals with chronic disease.
CNS infection can lead to HIV-associated neurocognitive disor-
ders (HAND), which remain common despite potent combina-
tion antiretroviral therapy (ART) (8). HIV and the resulting im-
mune and glial responses are likely to be important factors in the
pathogenesis of HAND, leading to structural and functional syn-
aptodendritic changes (15). Supporting the importance of the vi-
rus in the pathogenesis of HAND, HIV RNA concentrations in
CSF are higher in patients with cognitive impairment than in
those without impairment in cross-sectional and longitudinal
studies (6, 7, 16), although the association has weakened in the
highly active ART (HAART) era (20).
Antiretroviral drugs differ in their distribution—or penetra-
tion—into the CNS, with some drugs penetrating at concentra-
concentrations in the CNS should be able to reduce HIV replica-
solubility, protein binding, and transmembrane transport all af-
fect CNS penetration of antiretrovirals. Antiretrovirals that reach
higher levels in CSF are associated with better control of HIV
replication (10, 14) and often with better neurocognitive perfor-
mance (4, 12, 13, 21), although not all reports agree (14).
HIV protease inhibitors are highly bound to plasma proteins
tease inhibitors have the lowest fractional penetrance (i.e., the
amount of drug reaching the CSF compartment) into CSF of the
antiretroviral drug classes. The limited distribution of protease
inhibitors into the CNS may be mitigated by the substantial po-
tency of these drugs. One protease inhibitor, fosamprenavir
(FPV), a phosphorylated prodrug of amprenavir (APV), has low
plasma protein binding (90%) relative to other drugs in its class.
The objectives of this study were to measure APV concentrations
in CSF, to compare them with matched plasma concentrations,
and to estimate the efficacy of APV in the CNS by comparing the
drug’s concentrations in CSF to the in vitro 50% inhibitory con-
centration (IC50) range for wild-type HIV-1.
MATERIALS AND METHODS
CSF-plasma specimen pairs were selected from subjects who had HIV-1
infection and who had enrolled in parent observational cohort studies
conducted at or coordinated by the University of California, San Diego,
between July 2004 and January 2009. An optional lumbar puncture was
part of the design of those parent studies. These cohort studies included
the CNS HIV AntiRetroviral Therapy Effects Research (CHARTER) and
the California NeuroAIDS Tissue Network (CNTN) projects. Selection
criteria included use of FPV and availability of stored CSF and matched
(for FPV once-daily dosing) of self-reported dosing. Oral FPV was dosed
at 700 mg twice daily with ritonavir (RTV) 100 mg twice daily (n ? 62),
1,400 mg once daily with ritonavir 200 mg once daily (n ? 34), or 1,400
mg twice daily without RTV (n ? 23). The UCSD Human Research Pro-
from all subjects.
CSF was obtained by lumbar puncture performed with an aseptic
Blood was obtained within 1 h of CSF by routine phlebotomy. All speci-
Received 23 August 2011 Returned for modification 30 November 2011
Accepted 15 January 2012
Published ahead of print 30 January 2012
Address correspondence to David Croteau, firstname.lastname@example.org.
Copyright © 2012, American Society for Microbiology. All Rights Reserved.
0066-4804/12/$12.00Antimicrobial Agents and Chemotherapyp. 1985–1989aac.asm.org
mens were stored at ?70°C until analysis. Total APV was measured by
chromatography tandem mass spectrometry (LC/MS/MS) (in CSF). The
dynamic ranges of these assays were 3.9 to 2,000 ng/ml (plasma) and 0.39
to 200 ng/ml (CSF). APV concentrations in CSF were compared to the in
vitro IC50range for wild-type HIV, including the median (5.6 ng/ml) and
the 99th percentile (16.7 ng/ml) of the IC50range (17). HIV RNA was
assay (Roche Diagnostics) with a lower limit of detection of 50 copies/ml
cytometry. Adequate adherence was defined as subjects taking ?95% of
their scheduled antiretroviral drugs over 4 days preceding the CSF and
blood specimen collection and was based on self-reporting. Data were
analyzed with descriptive, bivariable, and multivariable statistics using
standard methods (JMP; SAS Institute, Cary, NC). Spearman’s correla-
tion coefficient was used to assess the relationship between plasma and
CSF APV concentrations. Descriptive statistics were calculated using all
data available. To eliminate bias due to interindividual differences in the
ysis comparing dosing schedule to APV concentrations, were limited to
one time point per subject. By convention, we selected the earliest time
point for each subject for these analyses.
A total of 119 CSF-plasma pairs were obtained from 75 subjects.
Most subjects provided either one (n ? 52) or two (n ? 14) spec-
imen pairs. The remaining 9 subjects provided 3 (n ? 5), 4 (n ?
1), 5 (n ? 1), 6 (n ? 1), and 9 (n ? 1) pairs. Subjects were pre-
dominantly middle-aged (median age of 44 years; interquartile
The median CD4?cell count at the time of sampling was 413/
mm3(IQR, 279 to 542), with 11% of values falling below 200/
mm3. The median nadir CD4?cell count was 105/mm3(IQR, 15
to 227). Disease severity based on the 1993 Centers for Disease
detection limit (1.70 log10copies/ml) in 57% of plasma and 88%
of CSF specimens.
The median duration of FPV use was 9.5 months (IQR, 3.1 to
20.1). Concurrent antiretrovirals included nucleoside or nucleo-
NRTI in 13%, an additional protease inhibitor other than ritona-
dose before sampling was taken with food at 83% of the sampling
time points, and adequate adherence was reported for 75 (87%).
APV concentrations in plasma and CSF are displayed in Fig. 1,
and aggregate data are summarized in Table 1, including both
overall results and results by FPV dosing schedule. APV was not
detected in four CSF specimens, while the corresponding plasma
had detectable APV. The median CSF APV concentrations with
and without RTV (including both FPV dosing schedules) were
(IQR, 10.7 to 41.5), respectively. The data for the timing of CSF
sampling were evenly distributed over the dosing intervals, and
the median postdose sampling intervals (? standard deviation
[SD]) were 7.2 ? 5.2 h for CSF and 6.9 ? 5.2 h for plasma. APV
was detectable in all but four CSF specimens. CSF fractional pen-
etrance (i.e., the amount of drug reaching the CSF compartment)
was 1.2% of the median total plasma APV concentration (IQR,
0.8% to 1.8%). APV concentrations in CSF correlated with those
in plasma (rho ? 0.61; P ? 0.0001) (Fig. 2) with persistent statis-
tical significance in subgroups with (rho ? 0.63; P ? 0.0001) and
without (rho ? 0.57; P ? 0.005) RTV. Further, correlations re-
mained consistently strong when correlative analyses were per-
formed using postdose sampling interval quartiles ranging from
0.5 to 5, 5 to 7, 7 to 12, and 12 to 23 h. The correlation weakened
slightly for the shortest postdose sampling interval range of 0.5 to
not statistically significant (P ? 0.123). APV concentrations in
plasma and CSF correlated with the postdose sampling interval
The CSF-to-plasma ratio did not change significantly across the
dosing interval (rho ? ?0.12; P ? 0.22). RTV-boosted FPV reg-
imens were associated with higher plasma concentrations of APV
inclusion of a single time point for subjects with multiple CSF-
type HIV-1 in 97.3% of specimens with detectable APV by a me-
dian of 4.4-fold (IQR, 2.9 to 7.9), while 73.9% of the same speci-
mens had concentrations above the 99th percentile of the IC50
range. Higher APV concentrations in plasma were not associated
Overall, higher APV concentrations in CSF were not associated
HIV RNA levels in CSF were undetectable when HIV RNA levels
detectable HIV RNA levels in plasma, detectable HIV RNA levels
in CSF trended toward an association with lower APV concentra-
analyses that accounted for APV concentrations in plasma, dura-
tion of FPV therapy, and postdose sampling time. Classification
and regression trees showed that all of the detectable HIV RNA
FIG 1 Amprenavir concentrations by fosamprenavir dosing schedule in
plasma (dark shading) and CSF (light shading) by postdose sampling time.
The horizontal solid line represents the median IC50(5.6 ng/ml) and the hor-
izontal dashed line the IC5099th percentile (16.7 ng/ml). Plasma concentra-
tions below 300 ng/ml and corresponding CSF data were excluded from the
Croteau et al.
aac.asm.orgAntimicrobial Agents and Chemotherapy
CSF below 53.5 ng/ml. This equated to a CSF-to-IC50ratio of 9.6.
In other words, all detectable HIV RNA levels in CSF occurred in
subjects whose APV concentrations in CSF exceeded the 50% in-
hibitory concentration by less than 9.6-fold. This categorical ex-
pression of CSF APV concentrations was statistically significantly
associated with detectable HIV RNA levels in CSF (? ? ?12.5;
P ? 0.01) in multivariable analyses that accounted for APV con-
centrations in plasma, duration of FPV therapy, and postdose
FPV dosing schedules were associated with different CSF and
IC50ratios as shown in Table 1 and Fig. 3. While FPV at 700 mg
BID with RTV resulted in the highest median CSF APV concen-
tration, the other FPV dosing schedules did not substantially dif-
fer. However, FPV at 1,400 mg BID without RTV had the highest
at 1,400 mg BID without RTV appeared to be associated with
lower plasma APV concentrations, although the differences com-
pared to other dosing schedules were not statistically significant.
than in a much smaller series with a median CSF APV concentra-
tion comparable to the one reported here (19). In this study, APV
concentrations in plasma were somewhat variable whereas APV
concentration required to inhibit wild-type HIV in vitro in nearly
all specimens regardless of dosing schedules (median, 4.4-fold
TABLE 1 Summary of amprenavir concentrations and sampling by fosamprenavir dosing schedule
Amprenavir concn (ng/ml) or IQR
or IQR CSFPlasma (overall)
FPV 700 mg BID, with RTV
FPV 1,400 mg once a day, with RTV
FPV 1,400 mg BID, no RTV
FPV 700 mg BID, with RTV
FPV 1,400 mg once a day, with RTV
FPV 1,400 mg BID, no RTV
FPV 700 mg BID, with RTV
FPV 1,400 mg once a day, with RTV
FPV 1,400 mg BID, no RTV
FIG 2 Correlation between amprenavir CSF and plasma concentrations.
FIG 3 CSF-to-plasma ratios of amprenavir concentrations by fosamprenavir
dosing schedule, including only the first time point for subjects with multiple
time points. QD, once daily.
Therapeutic Amprenavir Concentrations in CSF
April 2012 Volume 56 Number 4 aac.asm.org 1987
higher). In addition, the majority of specimens exceeded the 99th
percentile of the IC50range. The concentrations of APV in CSF
were lower than expected based on the drug’s physicochemical
characteristics. For example, APV has a relatively low binding
(90%) to plasma proteins such as albumin and alpha-1 acid gly-
coprotein compared to other drugs in its class (18). Therefore,
assuming all unbound drug penetrates into the CSF, one would
expect the CSF concentrations to be approximately 10% of those
in plasma. The lower-than-expected CSF fractional penetrance of
1.2% indicates that limiting factors restrict distribution of APV
into the CSF, which is similar to what has been seen previously
with other protease inhibitors (2, 3, 11). APV affinity for active
efflux transporters such as P-glycoprotein may be one of those
barriers (1, 22). Despite this limitation, the CSF fractional pen-
etrance still compares well to that of other protease inhibitors.
The moderate-to-strong correlation between APV concentra-
tions in CSF and plasma suggests that APV concentrations in
plasma would be useful for estimating concentrations in the CNS
and suggests that interventions focused on increasing APV con-
pling interval quarter may indicate the presence of some system
hysteresis for the CSF compartment, particularly at the beginning
of the dosing interval, perhaps suggesting achievement of mini-
mum concentrations in CSF while plasma concentrations are ris-
ing. The finding of a low proportion of CSF specimens with de-
APV in the CNS. However, the latter should not necessarily be
other antiretroviral agents in each drug regimen, may have ac-
counted for the finding. Disease-related variables may have also
good immune reconstitution (89% had CD4?T-cell counts ?
to originate from migrating lymphocytes (i.e., a predominant
blood source) than from macrophages and microglia in brain tis-
sue (i.e., a predominant CNS source) (5, 23).
tion of RTV may increase APV concentrations in plasma to a
this finding are possible. Active efflux transporters at the level of
der conditions of lower APV concentrations in plasma, with the
of the CNS. A non-mutually exclusive explanation is that active
concentrations of substrate or as result of RTV induction. One
possible conclusion from this finding is that higher doses of un-
boosted FPV may result in higher APV concentrations in CSF,
which may better ensure suppression of HIV replication in the
CNS. Four specimens had APV below the lower limit of quantita-
val (postdose sampling intervals of 2.0, 2.1, 6.2, and 7.8 h), possi-
bly suggesting that those may represent the minimum CSF
concentration ([Cmin] as opposed to the trough concentration.
This may be the result of system hysteresis pertaining to the CSF
plasma concentrations. Subjects with these low levels of APV in
CSF early in the postdose interval were no more likely to use one
dosing schedule of FPV than another.
Compared to other protease inhibitors, FPV appears to have
intermediate distribution into the CNS based on fractional pen-
etrance (higher than atazanavir penetrance and lower than indi-
navir or darunavir penetrance). APV’s CSF-to-IC50ratio is nu-
higher than that of atazanavir, but the clinical value of this mea-
sure is unproven (2, 3, 11). Even though APV has the lowest mo-
lecular weight of the HIV protease inhibitors currently in use and
a relatively high unbound fraction—characteristics that should
favor excellent CSF distribution—these characteristics may be
er’s affinity for APV. Despite these findings, more than 97% of
imens had undetectable HIV RNA (often when HIV RNA was
detectable in plasma), supporting the idea of APV’s antiviral ef-
fectiveness in the CNS, although other antiretrovirals may have
been contributing to those findings.
In summary, our findings provide supporting evidence that
APV reaches therapeutic concentrations in the CNS and, there-
fore, that FPV should be an effective component of antiretroviral
regimens that aim to control HIV replication in this pharmaco-
logically restricted compartment. The data presented in this re-
port support an intermediate position for fosamprenavir relative
ness, but this conclusion requires validation with a clinical trial
This study was supported by an investigator-initiated research grant
from GlaxoSmithKline and by the National Institutes of Health via
the following awards: N01 MH22005, HHSN271201000027C, and
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Therapeutic Amprenavir Concentrations in CSF
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