title: Steady-state pharmacokinetics of indinavir in cerebrospinal fluid and plasma among adults with human immunodeficiency virus type 1 infection.
abstract: To characterize steady-state indinavir pharmacokinetics in cerebrospinal fluid and plasma, 8 adults infected with human immunodeficiency virus underwent intensive cerebrospinal fluid sampling while receiving indinavir (800 mg every 8 hours) plus nucleoside reverse transcriptase inhibitors. Nine and 11 serial cerebrospinal fluid and plasma samples, respectively, were obtained from each subject. Free indinavir accounted for 94.3% of the drug in cerebrospinal fluid and 41.7% in plasma. Mean values of cerebrospinal fluid peak concentration, concentration at 8 hours, and area under the concentration-time profile calculated over the interval 0 to 8 hours [AUC(0-8)] for free indinavir were 294 nmol/L, 122 nmol/L, and 1616 nmol/L x h, respectively. The cerebrospinal fluid-to-plasma AUC(0-8) ratio for free indinavir was 14.7% +/- 2.6% and did not correlate with indexes of blood-brain barrier integrity or intrathecal immune activation. Indinavir achieves levels in cerebrospinal fluid that should contribute to control of human immunodeficiency virus type 1 replication in this compartment. The cerebrospinal fluid-to-plasma AUC(0-8) ratio suggests clearance mechanisms in addition to passive diffusion across the blood-cerebrospinal fluid barrier, perhaps by P-glycoprotein-mediated efflux.
authors.affiliation: Department of Medicine, Vanderbilt University School of Medicine, Nashville , Tenn 37212, USA.
authors.forename: D W
authors.initials: DW
authors.lastname: Haas
authors.forename: J
authors.initials: J
authors.lastname: Stone
authors.forename: L A
authors.initials: LA
authors.lastname: Clough
authors.forename: B
authors.initials: B
authors.lastname: Johnson
authors.forename: P
authors.initials: P
authors.lastname: Spearman
authors.forename: V L
authors.initials: VL
authors.lastname: Harris
authors.forename: J
authors.initials: J
authors.lastname: Nicotera
authors.forename: R H
authors.initials: RH
authors.lastname: Johnson
authors.forename: S
authors.initials: S
authors.lastname: Raffanti
authors.forename: L
authors.initials: L
authors.lastname: Zhong
authors.forename: P
authors.initials: P
authors.lastname: Bergqwist
authors.forename: S
authors.initials: S
authors.lastname: Chamberlin
authors.forename: V
authors.initials: V
authors.lastname: Hoagland
authors.forename: W D
authors.initials: WD
authors.lastname: Ju
mesh_terms: D000163:Acquired Immunodeficiency Syndrome / Q000097:blood* / Q000134:cerebrospinal fluid* / Q000188:drug therapy; D000284:Administration, Oral; D000328:Adult; D019540:Area Under Curve; D001812:Blood-Brain Barrier / Q000187:drug effects; D004334:Drug Administration Schedule; D017320:HIV Protease Inhibitors / Q000008:administration & dosage / Q000097:blood / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics* / Q000627:therapeutic use; D015497:HIV-1 / Q000235:genetics; D006801:Humans; D019469:Indinavir / Q000008:administration & dosage / Q000097:blood / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics* / Q000627:therapeutic use; D012333:RNA, Messenger / Q000097:blood; D012367:RNA, Viral / Q000097:blood
chemical_list: D017320:HIV Protease Inhibitors; D012333:RNA, Messenger; D012367:RNA, Viral; D019469:Indinavir