Comparison of two indinavir/ritonavir regimens in the treatment of HIV-infected individuals.
BACKGROUND
Pharmacokinetic enhancement of protease inhibitors (PIs) with low-dose ritonavir (RTV) for salvage therapy is increasingly common. The purpose of this study was to compare the pharmacokinetics, safety, and tolerability of indinavir (IDV)/RTV at 800/200 mg (arm A) and 400/400 mg (arm B) administered twice daily in HIV-infected subjects failing their first PI-based regimen.


METHODS
A phase I/II, randomized, open-label, 24-week study was conducted. Formal 12-hour pharmacokinetic evaluations were performed, and study visits occurred at baseline; at weeks 1, 2, and 4; and every 4 week thereafter for 24 weeks. Clinical symptoms and laboratory assessments were collected. Subjects were allowed to switch arms because of toxicity.


RESULTS
Forty-four subjects were enrolled (22 per arm). IDV predose concentration, maximum plasma concentration and area under the curve were significantly higher in arm A. Fifty-five percent and 45% of subjects in arms A and B responded (<200 copies/mL at week 24; P = 0.76), respectively. CD4 cell responses were similar. All subjects had IDV-sensitive virus at baseline and at virologic failure. Tolerability was comparable, but all grade 3 or higher triglyceride increases occurred in arm B and more subjects in arm B switched because of toxicity (5 vs. 1 triglyceride increases).


CONCLUSIONS
This is the largest formal pharmacokinetic evaluation of 2 dosage combinations of IDV/RTV in HIV-infected individuals. Pharmacokinetic parameters were consistent with previous results in patients but lower than in seronegative controls. Both regimens exhibited similar tolerability and response rates. High toxicity with a low response suggests that the optimum IDV/RTV combination would include an RTV dose <400 mg and an IDV dose <800 mg in this population.
Acosta
Edward P
EP
Division of Clinical Pharmacology, University of Alabama at Birmingham School of Medicine, Birmingham, AL 35294-0019, USA. EAcosta@uab.edu
Wu
Hulin
H
Hammer
Scott M
SM
Yu
Song
S
Kuritzkes
Daniel R
DR
Walawander
Ann
A
Eron
Joseph J
JJ
Fichtenbaum
Carl J
CJ
Pettinelli
Carla
C
Neath
Denise
D
Ferguson
Elaine
E
Saah
Alfred J
AJ
Gerber
John G
JG
D000293:Adolescent; D000328:Adult; D018791:CD4 Lymphocyte Count; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D005006:Ethnicity; D005260:Female; D015658:HIV Infections / Q000097:blood / Q000188:drug therapy* / Q000276:immunology; D017320:HIV Protease Inhibitors / Q000627:therapeutic use*; D015497:HIV-1 / Q000235:genetics / Q000302:isolation & purification; D006801:Humans; D019469:Indinavir / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D012367:RNA, Viral / Q000097:blood / Q000235:genetics; D019438:Ritonavir / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D015819:Substance Abuse, Intravenous / Q000150:complications / Q000453:epidemiology; D019562:Viral Load
D017320:HIV Protease Inhibitors; D012367:RNA, Viral; D019469:Indinavir; D019438:Ritonavir