Rik C. Schoemaker, Joop M.A. van Gerven & Adam F. Cohen
Centre for Human Drug Research, Zernikedreef 10, 2333CL Leiden, The Netherlands
The most widely applied model relating drug-concentrations to effects is the Emax model. In practice, concentration-effect relationships often deviate from a simple linear relationship but without reaching a clear maximum because a further increase in concentration might be associated with unacceptable or distorting side-effects. The parameters for the Emax model can only be estimated with reasonable precision if the curve shows signs of reaching a maximum, otherwise both EC50 and Emax estimates may be extremely imprecise. A solution is provided by introducing a new parameter (S0) equal to Emax/EC50 that can be used to adequately characterise potency even if there are no signs of a clear maximum. This parameter is equal to the slope of the tangent to the Emax curve at zero concentrations, which is very similar to the straight line that could be fitted to the initial (apparently straight) part of the concentration effect curve. Eight different simulations were carried out to compare the performance of S0 to Emax and EC50 estimates in various degrees of truncation of the Emax curve. Coefficients of variation for the S0 estimates were invariably (much) lower than corresponding Emax and EC50 estimates, and bias was either comparable or less. Two examples regarding sedation after intravenous administration of two new benzodiazepines were analysed using the S0 parameter. For one of the drugs (Ro 48-6791), a fourteen-fold difference in potency with midazolam was detected. The other drug (Ro 48-8684) indicated a two and a half-fold increase in sensitivity upon comparing a high dose (10mg) with a low dose (1 mg). These results indicate that the S0 parameter, in contrast with the EC50 and Emax, can be used to adequately characterise potency of drugs with only partial Emax curves.
Reference: PAGE 7 (1998) Abstr 278 [www.page-meeting.org/?abstract=278]
Poster: oral presentation