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Antimicrobial Agents and Chemotherapy, July 2003, p. 2131-2137, Vol. 47, No. 7
0066-4804/03/$08.00+0     DOI: 10.1128/AAC.47.7.2131-2137.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Effects of Ritonavir on Indinavir Pharmacokinetics in Cerebrospinal Fluid and Plasma

Division of Infectious Diseases, Department of Medicine,¹ Department of Microbiology and Immunology,² Department of Anesthesiology, Vanderbilt University School of Medicine,³ The Comprehensive Care Center, Nashville, Tennessee,⁴ Merck & Co., Inc., West Point, Pennsylvania⁵

Received 10 December 2002/ Returned for modification 17 March 2003/ Accepted 31 March 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 6,502 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.

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