Indinavir concentrations and antiviral effect

Study Objectives. To determine the variability of indinavir pharmacokinetic s in patients attending an outpatient clinic, and to explore relationships between indinavir exposure and antiviral effect. Design. Open, formal pharmacokinetic evaluation. Setting. University-affiliated clinical research center. Patients. Forty-three adults infected with the human immunodeficiency virus (HIV) receiving therapy with indinavir and concomitant nucleoside reverse transcriptase inhibitors. Intervention. Indinavir concentrations were measured after patients were ob served taking an 800-mg oral dose, and pharmacokinetic parameters were dete rmined using a one-compartment oral absorption model. Virologic and pharmac ologic characteristics were compared in a subset of 23 patients who were pr otease inhibitor naive before receiving indinavir. Measurements and Main Results. Mean indinavir pharmacokinetics were similar to those reported previously. Significant intersubject variability in syst emic exposure was observed in patients receiving the same dosage; the 8-hou r area under the curve (AUC(8)) ranged from 5.4-68.0 mu M . hour. In protea se inhibitor-naive subjects, the indinavir AUC(8) was statistically higher in those with undetectable plasma HIV RNA (30.7 mu M . hr) versus detectabl e plasma HIV RNA (22.4 mu M . hr, p=0.035). Measured concentrations 5 hours after the dose and extrapolated 8-hour concentrations were also significan tly higher in patients with undetectable plasma HIV RNA (both p=0.007). Conclusions. Indinavir plasma concentrations were highly variable among pat ients receiving the same dosage. Patients with an undetectable plasma HIV R NA level who were protease inhibitor naive had statistically higher indinav ir 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 hete rogeneity in therapeutic response.