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.

Effects of Ritonavir on Indinavir Pharmacokinetics in Cerebrospinal Fluid and Plasma

“…In a previous study we used a similar intensive sampling approach to characterize CSF and plasma pharmacokinetics of indinavir in eight adults receiving indinavir three times daily (800 mg every 8 h) without ritonavir (17). Subjects in the present study had significantly lower CD4…”

“…Results of the present study were compared to our previous study of eight subjects receiving indinavir (800 mg every 8 h) without ritonavir, as described elsewhere (17). In that study, inclusion criteria included stable therapy with indinavir plus any two nucleoside analogues for at least 30 days and levels of HIV-1 RNA in plasma below the limits of detection within the prior 30 days and greater than 200 CD4…”

“…Ritonavir increases plasma AUCs, half-lives, and trough concentrations of indinavir and other protease inhibitors by inhibiting the 3A4 isoform of cytochrome P450 (13,20,25) and overcomes the negative effect of food on indinavir bioavailability. Comparing detailed pharmacokinetic data from our previous study (17) with data from the present study allowed the effect of ritonavir on indinavir disposition into CSF to be thoroughly characterized. Despite a lower total daily dose of indinavir, ritonavir provided CSF indinavir C max , C min , and AUC 0-24 values ca.…”

“…Sample collection methods were otherwise identical in these studies. Indinavir in CSF and plasma was quantitated by using a similar LC/ MS/MS assay with some modification in the extraction method, chromatographic column, and mobile phase (17). The limit of quantitation was unchanged, and the assay accuracy was similar between the two studies.…”

“…It penetrates relatively well into cerebrospinal fluid (CSF) when given at 800 mg every 8 h (17,30). In a previous study involving eight subjects who underwent intensive CSF sampling over entire dosing intervals while receiving indinavir (800 mg every 8 h) without ritonavir, the total indinavir levels in CSF exceeded 100 nM throughout the 8-h dosing interval in four subjects and during at least 85% of the dosing interval in seven subjects (17). In the present study, intensive CSF sampling was used to characterize steady-state indinavir pharmacokinetics in CSF and plasma among seven adults receiving indinavir (800 mg every 12 h) and ritonavir (100 mg every 12 h) twice daily.…”