Effect of protein binding on unbound atazanavir and darunavir cerebrospinal fluid concentrations

HIV‐1 protease inhibitors (PIs) exhibit different protein binding affinities and achieve variable plasma and tissue concentrations. Degree of plasma protein binding may impact central nervous system penetration. This cross‐sectional study assessed cerebrospinal fluid (CSF) unbound PI concentrations, HIV‐1 RNA, and neopterin levels in subjects receiving either ritonavir‐boosted darunavir (DRV), 95% plasma protein bound, or atazanavir (ATV), 86% bound. Unbound PI trough concentrations were measured using rapid equilibrium dialysis and liquid chromatography/tandem mass spectrometry. Plasma and CSF HIV‐1 RNA and neopterin were measured by Ampliprep/COBAS® Taqman® 2.0 assay (Roche) and enzyme‐linked immunosorbent assay (ALPCO), respectively. CSF/plasma unbound drug concentration ratio was higher for ATV, 0.09 [95% confidence interval (CI) 0.06–0.12] than DRV, 0.04 (95%CI 0.03–0.06). Unbound CSF concentrations were lower than protein adjusted wild‐type inhibitory concentration‐50 (IC50) in all ATV and 1 DRV‐treated subjects (P