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

Abstract

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 < 0.001). CSF HIV-1 RNA was detected in 2/15 ATV and 4/15 DRV subjects (P = 0.65). CSF neopterin levels were low and similar between arms. ATV relative to DRV had higher CSF/plasma unbound drug ratio. Low CSF HIV-1 RNA and neopterin suggest that both regimens resulted in CSF virologic suppression and controlled inflammation.

Keywords: HIV/AIDS; central nervous system; clinical pharmacology.

Figure 1

Relationships between plasma and cerebrospinal fluid (CSF) unbound drug concentrations for atazanavir (ATV) and darunavir (DRV). (a) ATV (blue diamonds), Spearman rank correlation coefficient r = 0.77, P < 0.01, and (b) DRV (red diamonds), Spearman rank correlation coefficient r = 0.72, P < 0.01.

Figure 2

Mean cerebrospinal fluid (CSF) unbound trough concentration, standardized for each drug's wild-type protein-unbound IC₅₀ (ATV = 1.7 ng/mL and DRV = 0.4 ng/mL) between ATV (n = 13) and DRV (n = 14). Mean unbound ATV CSF concentration was less than half of the IC₅₀—ATV CSF concentration/IC₅₀ ratio was 0.4 (standard error 0.1). In contrast, mean DRV CSF concentration was 8 times greater than IC₅₀—mean DRV CSF concentration/IC₅₀ ratio was 8.0 (standard error 2.1).