Therapeutic Amprenavir Concentrations in Cerebrospinal Fluid

Croteau, David; Letendre, Scott; Best, Brookie M.; Rossi, Steven S.; Ellis, Ronald J.; Clifford, David B.; Collier, Ann C.; Gelman, Benjamin B.; Marra, Christina M.; McArthur, Justin C.; McCutchan, J. Allen; Morgello, Susan; Simpson, David M.; Way, Lauren; Capparelli, Edmund V.; Grant, Igor

doi:10.1128/aac.05098-11

Cited by 14 publications

(8 citation statements)

References 23 publications

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“…na: no activation. ni: no inhibition. b Published CSF/plasma. − c Published p K a . − d A D : cross-sectional area determined by molecular modeling. e A D : cross-sectional area determined experimentally by means of surface activity measurement. …”

Section: Resultsmentioning

confidence: 99%

“…Interestingly, published data showed that efavirenz concentrations in CSF are similar to the free concentration in plasma, suggesting that only the unbound efavirenz diffuses across the BBB. 27 Compounds with large A D such as PI and maraviroc have low CSF/plasma ratios [30][31][32]34,35,37 as a result of their lower rate of passive influx compared to active efflux (Figures 6 and 7). Indinavir CSF/plasma ratio is paradoxically high, which has been attributed to its lower degree of protein binding.…”

Section: ■ Discussionmentioning

confidence: 99%

“…It has been suggested that drugs with low CSF/plasma ratios (i.e., PI, efavirenz, etravirine, raltegravir, maraviroc) had CSF concen-trations well above IC 50 and therefore were efficient in patients with HAND. 27,28,[30][31][32][33][34]36,37 However, clinical studies evaluating the efficacy of regimens combining only 2 PI (i.e., boosted PI monotherapy) failed to show suppression of HIV replication in the CSF whereas systemic levels were undetectable. 56−58 Interestingly, the addition of 2 NRTI led to CSF viral suppression.…”

Section: Molecular Pharmaceuticsmentioning

confidence: 99%

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The Brain Entry of HIV-1 Protease Inhibitors Is Facilitated When Used in Combination

et al. 2013

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One hypothesis for persisting HIV-associated neurocognitive disorders (HAND) in effectively treated individuals is the limited permeation of antiretroviral agents (ARV) across the blood-brain barrier (BBB). However, the physicochemical factors limiting the brain entry of a given ARV and the mutual interactions of combined drugs on their brain entry have not been properly characterized. Using transporter kinetic measurements, we show that large lipophilic drugs such as protease inhibitors (PI) have strong binding affinities to drug efflux transporters expressed at the BBB and thus are prevented from entering the brain. However, when combined, the PI with the highest binding affinity (i.e., boosting ritonavir) will occupy a large proportion of the transporter binding sites and thus slow down the efflux rate of the coadministered PI thereby facilitating its brain entry. Furthermore, using thermodynamic measurements and computational modeling, we show that ARV with small cross-sectional areas (AD < 70 Å(2)) and octanol-water distribution coefficients (-1 < log D <5) such as most nucleoside analogues have a high passive influx and cross the BBB despite interactions with drug transporters. These data indicate that HIV therapies combining small diffusing molecules with large lipophilic molecules are better suited for brain entry and should be preferred for HAND. This work highlights the role of PI as modulators of drugs' brain entry.

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Section: Resultsmentioning

confidence: 99%

Section: ■ Discussionmentioning

confidence: 99%

Section: Molecular Pharmaceuticsmentioning

confidence: 99%

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The Brain Entry of HIV-1 Protease Inhibitors Is Facilitated When Used in Combination

et al. 2013

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“…Like ATV, CSF concentrations did not differ if ritonavir was administered concomitantly, in contrast with the findings in plasma, where drug concentrations were significantly higher in patients taking fAPV/r. 65 Although the above studies provide useful information in terms of PI levels achieved in the CSF, they have mainly involved patients receiving these drugs as part of triple cART regimens, thus precluding comparisons between drug level and virological efficacy in the CSF. It is a priority, for LDR studies of CNS efficacy, to establish whether there is an association between drug levels in CSF and plasma and virological outcomes in the CSF in patients receiving PIs as monotherapy.…”

Section: Achieving Inhibitory Intrathecal Pi Levels: Cerebrospinal Flmentioning

confidence: 99%

Central Nervous System HIV Infection in “Less-Drug Regimen” Antiretroviral Therapy Simplification Strategies

et al. 2014

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Less-drug regimens (LDR) refer to combinations of either two antiretroviral drugs or ritonavir-boosted protease inhibitor (PI) monotherapy. They may represent a simplification strategy in patients with persistently suppressed human immunodeficiency virus (HIV) viremia, with the main benefits of reducing drug-related toxicities and costs. Systemic virological efficacy of LDR is slightly lower as compared with combined antiretroviral therapy (cART), but patients with failure do not usually develop drug resistance and resuppress HIV replication after reintensification. A major concern of LDR is the lower efficacy in the virus reservoirs, especially in the central nervous system (CNS), where viral compartmentalization and independent evolution of infection may lead to CNS viral escape, often associated with neurologic symptoms. The authors reviewed studies of virological and functional CNS efficacy of LDR, particularly of boosted PI monotherapy regimens, for which more information is available. Symptomatic viral CSF escape was observed mainly in PI/r monotherapy patients with plasma failure and low nadir CD4+ cell counts, and resolved upon reintroduction of triple drug cART, whereas asymptomatic viral failure in CSF was not significantly more frequent in patients on PI/r monotherapy compared with patients on standard cART. In addition, there was no difference in functional outcomes between PI monotherapy and cART patients, irrespective of CSF viral escape. More data are needed on the CNS effect of dual ART regimens and, in general, on long-term efficacy of LDR. Simplification with LDR may be an attractive option in patients with suppressed viral load, if they are well selected and monitored for potential CNS complications.

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“…Ritonavir boosting was associated with higher plasma amprenavir concentrations, but not with higher CSF levels. The authors classified amprenavir with an intermediate ranking in relation to other PIs in terms of CNS penetration[65]. Darunavir is a very potent PI that effectively suppresses virus in both treatment-naïve and heavily treated patients.…”

Section: Pathogenesis Of Handmentioning

confidence: 99%

HIV-Associated Neurocognitive Disorders: Perspective on Management Strategies

Nabha

Duong

Timpone

2013

Drugs

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Potent combination antiretroviral therapy (ART) has resulted in dramatic improvement in AIDS associated morbidity and mortality. Although combination ART has resulted in a significant reduction in HIV associated dementia, the most severe form of HIV associated neurocognitive disorders (HAND), the overall prevalence of HAND among this population is estimated at 40%. It has been recognized that the central nervous system (CNS) serves as a reservoir for HIV, and neuronal damage begins at the time of acute infection and persists due to chronic infection of microglial and perivascular macrophages. Although combination ART has resulted in virologic control in the plasma compartment, virologic breakthrough can potentially ensue within the CNS compartment due to limited ART drug exposure. The purpose of this review is to discuss the definition, clinical spectrum and risk factors associated with HAND, review the pathogenesis of HAND, and address the pharmacologic challenges associated with ART drug exposure in the CNS compartment.

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Therapeutic Amprenavir Concentrations in Cerebrospinal Fluid

Cited by 14 publications

References 23 publications

The Brain Entry of HIV-1 Protease Inhibitors Is Facilitated When Used in Combination

The Brain Entry of HIV-1 Protease Inhibitors Is Facilitated When Used in Combination

Central Nervous System HIV Infection in “Less-Drug Regimen” Antiretroviral Therapy Simplification Strategies

HIV-Associated Neurocognitive Disorders: Perspective on Management Strategies

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