Effects of Ritonavir on Indinavir Pharmacokinetics in Cerebrospinal Fluid and Plasma
Open Access
- 1 July 2003
- journal article
- clinical trial
- Published by American Society for Microbiology in Antimicrobial Agents and Chemotherapy
- Vol. 47 (7), 2131-2137
- https://doi.org/10.1128/aac.47.7.2131-2137.2003
Abstract
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.Keywords
This publication has 29 references indexed in Scilit:
- Pharmacokinetic Profile and Tolerability of Indinavir-Ritonavir Combinations in Healthy VolunteersAntimicrobial Agents and Chemotherapy, 2001
- Evidence of a Source of HIV Type 1 within the Central Nervous System by Ultraintensive Sampling of Cerebrospinal Fluid and PlasmaAIDS Research and Human Retroviruses, 2000
- Factors That Predict Incomplete Virological Response to Protease Inhibitor‐Based Antiretroviral TherapyClinical Infectious Diseases, 1999
- Foscarnet Activity on Human Immunodeficiency Virus Type 1 in the Central Nervous SystemClinical Infectious Diseases, 1999
- Treatment of AIDS-associated progressive multifocal leukoencephalopathy with highly active antiretroviral therapyAIDS, 1998
- The drug transporter P-glycoprotein limits oral absorption and brain entry of HIV-1 protease inhibitors.JCI Insight, 1998
- Relationship between human immunodeficiency virus—associated dementia and viral load in cerebrospinal fluid and brainAnnals of Neurology, 1997
- L-735,524: The Design of a Potent and Orally Bioavailable HIV Protease InhibitorJournal of Medicinal Chemistry, 1994
- Pharmacokinetic evaluation of stable piecewise cubic polynomials as numerical integration functionsJournal of Pharmacokinetics and Biopharmaceutics, 1989
- EXPRESSION OF HUMAN IMMUNODEFICIENCY VIRUS ANTIGEN (HIV-Ag) IN SERUM AND CEREBROSPINAL FLUID DURING ACUTE AND CHRONIC INFECTIONThe Lancet, 1986