Effects of ritonavir on indinavir pharmacokinetics in cerebrospinal fluid and plasma.
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.
Haas
David W
DW
Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee 37212, USA. david.w.haas@vanderbilt.edu
Johnson
Benjamin
B
Nicotera
Janet
J
Bailey
Vicki L
VL
Harris
Victoria L
VL
Bowles
Farideh B
FB
Raffanti
Stephen
S
Schranz
Jennifer
J
Finn
Tyler S
TS
Saah
Alfred J
AJ
Stone
Julie
J
D000328:Adult; D019380:Anti-HIV Agents / Q000627:therapeutic use; D001812:Blood-Brain Barrier / Q000187:drug effects; D004359:Drug Therapy, Combination; D005260:Female; D015658:HIV Infections / Q000188:drug therapy*; D017320:HIV Protease Inhibitors / Q000097:blood / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics*; D006801:Humans; D007074:Immunoglobulin G / Q000134:cerebrospinal fluid; D019469:Indinavir / Q000097:blood / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics*; D019259:Lamivudine / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D019438:Ritonavir / Q000627:therapeutic use*; D018119:Stavudine / Q000627:therapeutic use
D019380:Anti-HIV Agents; D017320:HIV Protease Inhibitors; D007074:Immunoglobulin G; D019259:Lamivudine; D019469:Indinavir; D018119:Stavudine; D019438:Ritonavir