Indinavir concentrations and antiviral effect.
OBJECTIVE
To determine the variability of indinavir pharmacokinetics in patients attending an outpatient clinic, and to explore relationships between indinavir exposure and antiviral effect.


METHODS
Open, formal pharmacokinetic evaluation.


METHODS
University-affiliated clinical research center.


METHODS
Forty-three adults infected with the human immunodeficiency virus (HIV) receiving therapy with indinavir and concomitant nucleoside reverse transcriptase inhibitors.


METHODS
Indinavir concentrations were measured after patients were observed taking an 800-mg oral dose, and pharmacokinetic parameters were determined using a one-compartment oral absorption model. Virologic and pharmacologic characteristics were compared in a subset of 23 patients who were protease inhibitor naive before receiving indinavir.


RESULTS
Mean indinavir pharmacokinetics were similar to those reported previously. Significant intersubject variability in systemic exposure was observed in patients receiving the same dosage; the 8-hour area under the curve (AUC8) ranged from 5.4-68.0 microM x hour. In protease inhibitor-naive subjects, the indinavir AUC8 was statistically higher in those with undetectable plasma HIV RNA (30.7 microM x hr) versus detectable plasma HIV RNA (22.4 microM x hr, p=0.035). Measured concentrations 5 hours after the dose and extrapolated 8-hour concentrations were also significantly higher in patients with undetectable plasma HIV RNA (both p=0.007).


CONCLUSIONS
Indinavir plasma concentrations were highly variable among patients receiving the same dosage. Patients with an undetectable plasma HIV RNA level who were protease inhibitor naive had statistically higher indinavir concentrations and slower oral clearance than the group with detectable HIV RNA. Relationships between indinavir concentrations and anti-HIV effect provide a basis for quantifying the pharmacologic contribution to the heterogeneity in therapeutic response.
Acosta
E P
EP
College of Pharmacy, Department of Clinical Pharmacology, University of Minnesota Academic Health Sciences Center, Minneapolis 55455, USA.
Henry
K
K
Baken
L
L
Page
L M
LM
Fletcher
C V
CV
D000328:Adult; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D019540:Area Under Curve; D004305:Dose-Response Relationship, Drug; D005260:Female; D015658:HIV Infections / Q000097:blood / Q000188:drug therapy*; D017320:HIV Protease Inhibitors / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D006801:Humans; D019469:Indinavir / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D008297:Male
D019380:Anti-HIV Agents; D017320:HIV Protease Inhibitors; D019469:Indinavir