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 fl uid and plasma, 8 adults infected with human immunodeficiency virus underwe nt 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 obtain ed from each subject. Free indinavir accounted for 94.3% of the drug in cer ebrospinal fluid and 41.7% in plasma. Mean values of cerebrospinal fluid pe ak concentration, concentration at 8 hours, and area under the concentratio n-time profile calculated over the interval 0 to 8 hours [AUC(0-8)] for fre e indinavir were 294 nmol/L, 122 nmol/L and 1616 nmol/L . 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 integ rity or intrathecal immune activation. Indinavir achieves levels in cerebro spinal fluid that should contribute to control of human immunodeficiency vi rus type 1 replication in this compartment. The cerebrospinal fluid-to-plas ma AUC(0-8) ratio suggests clearance mechanisms in addition to passive diff usion across the blood-cerebrospinal fluid barrier, perhaps by P-glycoprote in-mediated efflux.