Indinavir protein-free concentrations when used in indinavir/ritonavir combination therapy.
OBJECTIVE
To describe the in vivo protein-binding characteristics of indinavir (IDV) in the presence of ritonavir (RTV) relative to total IDV plasma concentrations.


METHODS
The ACTG protocol 5055 was a multicenter study comparing the safety and pharmacokinetics of IDV/RTV at doses of 800/200 and 400/400 mg twice daily in HIV-infected adults.


METHODS
Forty-four patients underwent a 12-h intensive pharmacokinetic assessment after 2 weeks of therapy. Three plasma samples from 35 patients at Cmax, 6 and 12 h post dose were used to determine the unbound IDV concentrations. Unbound IDV was separated in plasma samples using ultra-filtration and measured using high-performance liquid chromatography with UV detection.


RESULTS
Mean IDV protein-bound fraction across all time points in the 800/200 and 400/400 arm were 53.4 and 51.8%, respectively. In the 800/200 arm, percentage binding at Cmax was 50% compared with 56% at 12 h (P = 0.008). In the 400/400 arm, percentage binding at Cmax was 49% compared with 54% at 12 h (P = 0.008).


CONCLUSIONS
The extent of plasma protein binding of IDV in this study was less than in previously published data with IDV alone. Although IDV concentrations differed across the arms, the percentage of IDV protein binding at all time points was not different between the 800/200 and 400/400 arms. However, the percentage of IDV protein binding at Cmax was significantly lower compared with 12 h in each arm, possibly suggesting that IDV protein binding is concentration-dependent. These data suggest that RTV affects IDV protein-binding characteristics and IDV also exhibits concentration dependent binding when administered with RTV.
King
Jennifer R
JR
University of Alabama at Birmingham, School of Medicine, Division of Clinical Pharmacology, Birmingham, Alabama, USA.
Gerber
John G
JG
Fletcher
Courtney V
CV
Bushman
Lane
L
Acosta
Edward P
EP
D000328:Adult; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D005260:Female; D015658:HIV Infections / Q000188:drug therapy*; D017320:HIV Protease Inhibitors / Q000008:administration & dosage / Q000378:metabolism*; D006801:Humans; D019469:Indinavir / Q000008:administration & dosage / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D011485:Protein Binding; D019438:Ritonavir / Q000008:administration & dosage / Q000378:metabolism*
D019380:Anti-HIV Agents; D004338:Drug Combinations; D017320:HIV Protease Inhibitors; D019469:Indinavir; D019438:Ritonavir