Modeling combinations of antiretroviral agents in vitro with integration of pharmacokinetics: guidance in regimen choice for clinical trial evaluation.
We propose a method for the selection of doses and dosing schedule for drugs to be used in combination. This approach uses the simulation of steady-state concentrations of the drugs in the combination and overlays these concentrations onto a three-dimensional effect surface. The MacSynergy II program is used to construct the three-dimensional drug interaction surface from the direct evaluation of drug combination effect in vitro. The study examined the combination of an inhibitor of the human immunodeficiency virus protease, A-77003, and the nucleoside analog zidovudine. Zidovudine concentrations from a steady-state interval were simulated on the basis of the administration of 100 mg every 12 h by mouth, while for A-77003 simulation profiles were for intravenous administration of 800 mg every 4 h as well as a continuous infusion of 200 mg/h. The average percentage of the maximal effect was taken as a measure of regimen effectiveness. Three different schedules of administration were examined. If both drugs were to be administered simultaneously, the model predicts a mean maximal effect of a steady-state interval (12 h) of 67%. If the drug doses were offset by 2 h, the mean maximal effect predicted was 71%. If A-77003 was to be given by continuous infusion, the mean maximal effect predicted was 90%. This method holds promise as a way of quickly evaluating potential combinations of agents that takes into account the drug interaction in a mathematically robust way and that allows the evaluation of the effect of each drug's pharmacokinetic profile.
Drusano
G L
GL
Department of Medicine, Albany Medical College, New York 12208, USA. GLDRU-SANO@AOL.COM
Prichard
M
M
Bilello
P A
PA
Bilello
J A
JA
D000998:Antiviral Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D002460:Cell Line; D017321:Clinical Trials, Phase I as Topic; D017322:Clinical Trials, Phase II as Topic; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D015658:HIV Infections / Q000188:drug therapy; D017320:HIV Protease Inhibitors / Q000494:pharmacology; D015497:HIV-1 / Q000187:drug effects; D008782:Methylurea Compounds / Q000008:administration & dosage* / Q000493:pharmacokinetics; D008954:Models, Biological; D009010:Monte Carlo Method; D011725:Pyridines / Q000008:administration & dosage* / Q000493:pharmacokinetics; D014633:Valine / Q000031:analogs & derivatives; D015215:Zidovudine / Q000008:administration & dosage* / Q000493:pharmacokinetics
D000998:Antiviral Agents; D017320:HIV Protease Inhibitors; D008782:Methylurea Compounds; D011725:Pyridines; D015215:Zidovudine; C079555:Abbott 77003; D014633:Valine