This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints and Permissions Copyright Information Books from ASM Press MicrobeWorld Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Drusano, G. L. Articles by Bilello, J. A. Search for Related Content PubMed PubMed Citation Articles by Drusano, G. L. Articles by Bilello, J. A.

 Previous Article  |  Next Article 

Antimicrobial Agents and Chemotherapy, May 1996, 1143-1147, Vol 40, No. 5
Copyright © 1996 by the American Society for Microbiology. All rights reserved.

Modeling combinations of antiretroviral agents in vitro with integration of pharmacokinetics: guidance in regimen choice for clinical trial evaluation

GL Drusano, M Prichard, PA Bilello and JA Bilello
Department of Medicine, Albany Medical College, New York 12208, USA. GLDRU-SANO@AOL.COM

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.

This article has been cited by other articles:

• Drusano, G. L., D'Argenio, D. Z., Symonds, W., Bilello, P. A., McDowell, J., Sadler, B., Bye, A., Bilello, J. A. (1998). Nucleoside Analog 1592U89 and Human Immunodeficiency Virus Protease Inhibitor 141W94 Are Synergistic In Vitro. Antimicrob. Agents Chemother. 42: 2153-2159 [Abstract] [Full Text]  
• den Hollander, J. G., Mouton, J. W., Verbrugh, H. A. (1998). Use of Pharmacodynamic Parameters To Predict Efficacy of Combination Therapy by Using Fractional Inhibitory Concentration Kinetics. Antimicrob. Agents Chemother. 42: 744-748 [Abstract] [Full Text]