Effects of ritonavir on indinavir pharmacokinetics in cerebrospinal fluid and plasma.

Haas DW, Johnson B, Nicotera J, Bailey VL, Harris VL, Bowles FB, Raffanti S, Schranz J, Finn TS, Saah AJ, Stone J
Antimicrob Agents Chemother. 2003 47 (7): 2131-7

PMID: 12821458 · PMCID: PMC161873 · DOI:10.1128/aac.47.7.2131-2137.2003

Therapeutic control of human immunodeficiency virus type 1 (HIV-1) in peripheral compartments does not assure control in the central nervous system. Inadequate drug penetration may provide a sanctuary from which resistant virus can emerge or allow development of psychomotor abnormalities. To characterize the effect of ritonavir on indinavir disposition into cerebrospinal fluid, seven HIV-infected adults underwent intensive sampling at steady-state while receiving twice-daily indinavir (800 mg) and ritonavir (100 mg). Serial cerebrospinal fluid and plasma samples were obtained at 10 time points from each subject. Free indinavir accounted for 98.6% of drug in cerebrospinal fluid and 55.9% in plasma. Mean cerebrospinal fluid C(max), C(min), and area under the concentration-time curve from 0 to 12 h (AUC(0-12)) values for free indinavir were 735 nM, 280 nM, and 6502 nM h(-1), respectively, and the free levels exceeded 100 nM in every sample. The cerebrospinal fluid/plasma AUC(0-12) ratio for free indinavir was 17.5% +/- 6.4%. This ratio was remarkably similar to results obtained in a previous study in which subjects received indinavir without ritonavir, indicating that ritonavir did not have a substantial direct effect on the barrier to indinavir penetration into cerebrospinal fluid. Low-dose ritonavir increases cerebrospinal fluid indinavir concentrations substantially more than 800 mg of indinavir given thrice daily without concomitant ritonavir, despite a lower total daily indinavir dose.

MeSH Terms (15)

Adult Anti-HIV Agents Blood-Brain Barrier Drug Therapy, Combination Female HIV Infections HIV Protease Inhibitors Humans Immunoglobulin G Indinavir Lamivudine Male Middle Aged Ritonavir Stavudine

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