Emax model and interaction index for assessing drug interaction in combination studies.
Applying the Emax model in a Lowe additivity model context, we analyze data from a combination study of trimetrexate (TMQ) and AG2034 (AG) in media of low and high concentrations of folic acid (FA). The Emax model provides a sufficient fit to the data. TMQ is more potent than AG in both low and high FA media. At low TMQ:AG ratios, when a smaller amount of the more potent drug (TMQ) is added to a larger amount of the less potent drug (AG), synergy results. When the TMQ:AG ratio reaches 0.4 or larger in low FA medium, or when the TMQ:AG ratio reaches 1 or larger in high FA medium, synergy is weakened and drug interaction becomes additive. In general, synergistic effect in a dilution series is stronger at higher doses that produce stronger effects (closer to 1-Emax) than at lower dose levels that produce weaker effects (closer to 1). The two drugs are more potent in the low compared to the high FA medium. Drug synergy, however, is stronger in the high FA medium.
Lee
J Jack
JJ
Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Unit 1411, 1515 Holcombe Boulevard, Houston, Texas 77030-1402, USA.
Lin
Heather Y
HY
Liu
Diane D
DD
Kong
Maiying
M
D003627:Data Interpretation, Statistical; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D015195:Drug Design; D004347:Drug Interactions; D005492:Folic Acid / Q000378:metabolism*; D005971:Glutamates / Q000378:metabolism / Q000494:pharmacology*; D011743:Pyrimidines / Q000378:metabolism / Q000494:pharmacology*; D016597:Trimetrexate / Q000378:metabolism / Q000494:pharmacology*
D004338:Drug Combinations; D005971:Glutamates; D011743:Pyrimidines; D005492:Folic Acid; C105066:AG 2034; D016597:Trimetrexate