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

Abstract

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.

Altered Oligodendrocyte Maturation and Myelin Maintenance: The Role of Antiretrovirals in HIV-Associated Neurocognitive Disorders

“…However, there is extensive evidence of HIV-mediated disruption of the blood brain barrier resulting in increased entry of normally excluded small molecules and serum proteins (61–63). In addition to HIV-mediated effects, even in the absence of virus, CNS accessibility is not necessarily as restricted as anticipated, as brain entry can be facilitated if the drugs are given in combination (64). Importantly, animal studies predict that parenchymal concentrations reach levels equal to, or greater than those found in the CSF, suggesting that concentrations attained in the human brain may be higher than current clinical estimates (65, 66).…”

“…Ritonavir is globally used clinically as a boost for other antiretrovirals to increase bioavailability because it is a potent inhibitor of cytochrome P450, which metabolizes these compounds (82). Increased bioavailability of co-administered compounds with high CNS penetrance likely leads to higher brain levels of these compounds (64). Additionally, Ritonavir-boosted regimens are still commonly prescribed in resource-limited settings as first-line treatment, making it globally among the most-prescribed treatment options (83).…”

Cerebrospinal fluid abacavir concentrations in HIV‐positive patients following once‐daily administration

“…PIs may influence drug penetration by inhibiting drug efflux transporters, such as P‐glycoprotein and breast cancer resistance protein, as shown in vitro by Marzolini et al . . Age may be a contributing factor in increasing drug concentration in the CSF, as increased BBB permeability, lower CSF production and reduced transporter function have been suggested to occur in older adults .…”

Nose to brain delivery of antiretroviral drugs in the treatment of neuroAIDS

“…It was observed that lipophilic drugs such as protease inhibitors (PI) have a high affinity for drug efflux transporter at BBB, thereby prevent their entry into the brain. However, in combination, the PIs of higher affinity will bind to the transporter and thereby preventing the efflux of the coadministered PIs that facilitate its brain entry [113]. To enhance drug delivery to the brain, various strategies such as non-invasive methods, including drug modification to its lipophilic analogues, pro-drugs, chemical drug delivery, carrier-mediated drug delivery, receptor/vectormediated drug delivery, and intranasal drug delivery are widely used [102,[114][115][116].…”