Pharmacodynamic modeling of the EEG effects of ketamine and its enantiomers in man

The pharmacodynamics of a racemic mixture of ketamine R,S(+/-)-ketamine and of each enantiomer, S(+)-ketamine and R(-)-ketamine, were studied in five volunteers. The median frequency of the electroencephalogram (EEG) power spectrum, a continuous noninvasive measure of the degree of central nervous system (CNS) depression (pharmacodynamics), was related to measured serum concentrations of drug (pharmacokinetics). The concentration-effect relationship was described by an inhibitory sigmoid Emax pharmacodynamic model, yielding estimates of both maximal effect (Emax) and sensitivity (IC50) to the racemic and enantiomeric forms of ketamine. R(-)-ketamine was not as effective as R,S(+/-)-ketamine or S(+)-ketamine in causing EEG slowing. The maximal decrease (mean +/- SD) of the median frequency (Emax) for R(-)-ketamine was 4.4 +/- 0.5 Hz and was significantly different from R,S(+/-)-ketamine (7.6 +/- 1.7 Hz) and S(+)-ketamine (8.3 +/- 1.9 Hz). The ketamine serum concentration that caused one-half of the maximal median frequency decrease (IC50) was 1.8 +/- 0.5 micrograms/mL for R(-)-ketamine; 2.0 +/- 0.5 micrograms/mL for R,S(+/-)-ketamine; and 0.8 +/- 0.4 microgram/mL for S(+)-ketamine. Because the maximal effect (Emax) of the R(-)-ketamine was different from that of S(+)-ketamine and R,S(+/-)-ketamine, it was not possible to directly compare the potency (i.e., IC50) of these compounds. Accordingly, a classical agonist/partial-agonist interaction model was examined, using the separate enantiomer results to predict racemate results. Although the model did not predict racemate results well, its failure was not so great as to provide clear evidence of synergism (or excess antagonism) of the enantiomers.