Low atazanavir concentrations in cerebrospinal fluid

Area of Science:

• Pharmacology
• Infectious Diseases
• Neuroscience

Background:

• Protease inhibitors (PIs) are crucial for HIV treatment.
• Limited central nervous system (CNS) penetration of PIs may hinder HIV control in the brain.
• Understanding drug concentrations in cerebrospinal fluid (CSF) is vital for assessing CNS efficacy.

Purpose of the Study:

• To quantify atazanavir penetration into the CSF.
• To evaluate the impact of ritonavir boosting on atazanavir CSF concentrations.
• To determine if atazanavir CSF levels are sufficient to inhibit HIV replication.

Main Methods:

• Observational cohort study of 117 participants on atazanavir with/without ritonavir.
• Paired plasma and CSF samples collected 10 hours postdose.
• Atazanavir concentrations measured using high-performance liquid chromatography and immunoassay.

Main Results:

• Median CSF atazanavir concentrations were 10.3 ng/ml (unboosted) and 7.9 ng/ml (ritonavir-boosted).
• CSF concentrations were <1% of plasma concentrations and highly variable.
• 24% of CSF samples had concentrations below the assay limit of detection (5 ng/ml).

Conclusions:

• Atazanavir CSF concentrations are substantially lower than plasma levels, even with ritonavir.
• These concentrations are near the 50% inhibitory concentration (IC50) for wild-type HIV.
• Atazanavir may not consistently achieve therapeutic levels in the CSF to prevent HIV replication.