Lopinavir concentrations in cerebrospinal fluid exceed the 50% inhibitory concentration for HIV

Abstract

In patients with typical plasma levels of LPV, the drug is detectable in the CSF at concentrations that exceed those needed to inhibit HIV replication. Despite being > 98% bound to plasma proteins, LPV penetrates into the CNS and may contribute to the control of HIV in this potential reservoir.

Therapeutic Amprenavir Concentrations in Cerebrospinal Fluid

“…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).…”

“…ϩ cell count at the time of sampling was 413/ mm 3 (IQR, 279 to 542), with 11% of values falling below 200/ mm 3 . The median nadir CD4 ϩ cell count was 105/mm 3 (IQR, 15 to 227).…”

“…APV's CSF-to-IC 50 ratio is numerically lower than that of lopinavir, darunavir, or indinavir and higher than that of atazanavir, but the clinical value of this measure is unproven (2,3,11). Even though APV has the lowest molecular 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 mitigated by APV's average liposolubility relative to those of other protease inhibitors and the P-glycoprotein active efflux transporter's affinity for APV.…”

Protein-Free Efavirenz Concentrations in Cerebrospinal Fluid and Blood Plasma Are Equivalent: Applying the Law of Mass Action To Predict Protein-Free Drug Concentration

“…Possible explanations for this include the CNS acting as a pharmacological sanctuary due to inadequate penetration of ARVs, toxicity due to ARV exposure with more-sensitive drug toxicity responses in the CNS, coinfection, or other neurological disorders, and physiological factors, including age and sex (10,13). Several ARVs achieve lower concentrations in cerebrospinal fluid (CSF) than in blood plasma (BP), though these concentrations may still exceed the in vitro 50% inhibitory concentration (IC 50 ) for HIV inhibition (14)(15)(16)(17). Still, ARVs that have poor CNS penetration are strongly associated with increased viral load in the CSF, and a CNS penetration effectiveness (CPE) score has been developed and refined as one among several explanatory variables of HAND (18).…”

Italian Consensus Statement on Management of HIV-Infected Individuals with Advanced Disease Naïve to Antiretroviral Therapy

“…Patients with neurocognitive disorders and/or detectable HIV-1 RNA levels in the CSF before cART has been started should be prescribed antiretroviral regimens containing neuroactive drugs with a high penetration score in CSF [68,73,74] (A-II). In the case of worsening clinical conditions and/or of neurocognitive tests, these patients should undergo lumbar puncture both to assess HIV-1 RNA levels in the CSF and to perform genotypic resistance test on the CSF virus in order to choose the most appropriate therapeutic option (B-III).…”