Steady-state pharmacokinetics of indinavir in cerebrospinal fluid and plasma among adults with human immunodeficiency virus type 1 infection.
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.
Haas
D W
DW
Department of Medicine, Vanderbilt University School of Medicine, Nashville , Tenn 37212, USA.
Stone
J
J
Clough
L A
LA
Johnson
B
B
Spearman
P
P
Harris
V L
VL
Nicotera
J
J
Johnson
R H
RH
Raffanti
S
S
Zhong
L
L
Bergqwist
P
P
Chamberlin
S
S
Hoagland
V
V
Ju
W D
WD
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
D017320:HIV Protease Inhibitors; D012333:RNA, Messenger; D012367:RNA, Viral; D019469:Indinavir