Effect of simultaneous versus staggered dosing on pharmacokinetic interactions of protease inhibitors.
OBJECTIVE
The aim of this study was to determine whether pharmacokinetic interactions between the protease inhibitors saquinavir soft gel, nelfinavir, and ritonavir are affected by the timing of administration.


METHODS
We used an open-label, 6-period, incomplete Latin square crossover study in 18 human immunodeficiency virus-negative subjects. Each received single oral doses of 2 of the 3 protease inhibitors during each of 6 periods. Single doses were given either simultaneously or separated by 4 hours. The order of the periods was balanced, and periods were separated by 2 days. We measured protease inhibitor concentrations over a 24-hour period by HPLC and estimated pharmacokinetic parameters by noncompartmental methods.


RESULTS
Median saquinavir area under the curve (AUC) increased by 62-fold when ritonavir was coadministered, by 50-fold when ritonavir was given 4 hours earlier, and by 16-fold when saquinavir preceded ritonavir by 4 hours. Saquinavir AUC increased by 7-fold when nelfinavir was coadministered. Nelfinavir AUC increased by 2.5-fold with coadministration of ritonavir and by 1.8- and 2.1-fold when ritonavir was administered before nelfinavir and after nelfinavir, respectively. Ritonavir AUCs were unaffected by coadministration of the other drugs. The effect of ritonavir on the kinetics of saquinavir persisted for at least 48 hours after a single dose of ritonavir, suggesting the possibility of metabolic intermediates that form inhibitory complexes.


CONCLUSIONS
Except for saquinavir followed by ritonavir, there is little difference in protease inhibitor exposure for simultaneous or staggered doses. The persistent effect of ritonavir suggests the possibility that lower doses and longer dosing intervals might be effective when ritonavir is used to boost concentrations of other protease inhibitors.
Washington
Carla B
CB
Department of Medicine, Stanford University Medical Center, Stanford, CA 94305-5130, USA.
Flexner
Charles
C
Sheiner
Lewis B
LB
Rosenkranz
Susan L
SL
Segal
Yoninah
Y
Aberg
Judith A
JA
Blaschke
Terrence F
TF
D000328:Adult; D019540:Area Under Curve; D002851:Chromatography, High Pressure Liquid; D018592:Cross-Over Studies; D004334:Drug Administration Schedule; D004338:Drug Combinations; D005260:Female; D017320:HIV Protease Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D006801:Humans; D008297:Male; D019888:Nelfinavir / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D019438:Ritonavir / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D019258:Saquinavir / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D013056:Spectrophotometry, Ultraviolet
D004338:Drug Combinations; D017320:HIV Protease Inhibitors; D019888:Nelfinavir; D019258:Saquinavir; D019438:Ritonavir