title: 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.
authors.affiliation: Division of Infectious, Diseases Department of Medicine, Emory University School of Medicine, Atlanta, GA, USA.
authors.forename: Cecile A
authors.initials: CA
authors.lastname: Delille
authors.forename: Sarah T
authors.initials: ST
authors.lastname: Pruett
authors.forename: Vincent C
authors.initials: VC
authors.lastname: Marconi
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Lennox
authors.forename: Wendy S
authors.initials: WS
authors.lastname: Armstrong
authors.forename: Richard F
authors.initials: RF
authors.lastname: Arrendale
authors.forename: Anandi N
authors.initials: AN
authors.lastname: Sheth
authors.forename: Kirk A
authors.initials: KA
authors.lastname: Easley
authors.forename: Edward P
authors.initials: EP
authors.lastname: Acosta
authors.forename: Aswani
authors.initials: A
authors.lastname: Vunnava
authors.forename: Ighovwerha
authors.initials: I
authors.lastname: Ofotokun
mesh_terms: D000328:Adult; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000097:blood / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics*; D000069446:Atazanavir Sulfate; D001798:Blood Proteins / Q000378:metabolism; D000069454:Darunavir; D004359:Drug Therapy, Combination; D005260:Female; D015658:HIV Infections / Q000097:blood / Q000134:cerebrospinal fluid / Q000378:metabolism / Q000821:virology; D015497:HIV-1 / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D019798:Neopterin / Q000097:blood / Q000134:cerebrospinal fluid; D009842:Oligopeptides / Q000008:administration & dosage / Q000097:blood / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics*; D011485:Protein Binding; D011725:Pyridines / Q000008:administration & dosage / Q000097:blood / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics*; D012367:RNA, Viral / Q000097:blood / Q000134:cerebrospinal fluid; D019438:Ritonavir / Q000008:administration & dosage; D013449:Sulfonamides / Q000008:administration & dosage / Q000097:blood / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics*
chemical_list: D019380:Anti-HIV Agents; D001798:Blood Proteins; D009842:Oligopeptides; D011725:Pyridines; D012367:RNA, Viral; D013449:Sulfonamides; D000069446:Atazanavir Sulfate; D019798:Neopterin; D019438:Ritonavir; D000069454:Darunavir
keywords: HIV/AIDS; central nervous system; clinical pharmacology