PHARMACOKINETIC-PHARMACODYNAMIC MODELING OF MEPERIDINE IN GOATS .2. MODELING

Simultaneous pharmacokinetic-pharmacodynamic (PK-PD) models of meperid ine in goats were established by utilizing the P3 wave of the cerebral evoked potentials as an analgesic measurement. An effect compartment linked to the central compartment was postulated in the models. The hy pothetical drug amount in the effect compartment was related to the ob served analgesia through the Hill equation. After intramuscular (i.m., n = 16) and intravenous (i.v., n = 13) dosing (5 mg/kg), the eliminat ion rate constants of meperidine in the effect compartment (K(e0)) wer e 0.3744 +/- 0.2546 and 0.1123 +/- 0.0428 min-1, drug concentrations i n the effect compartment generating half maximal analgesia (EC(50)) we re 0.70 +/- 0.33 and 0.41 +/- 0.26 mug/ml, the maximal effects (E(max) ) were 89.6 3 +/- 15.63 and 8 5.9 2 +/- 9.64%, and the Hill coefficien ts (S) were 2.61 +/- 1.21 and 2.37 +/- 1.15, respectively. K(e0) and E C(50) with i.m. dosing were significantly greater than with i.v. injec tion. However, administration route had no influence on S, E(max) and the total amount of effect (AUE). The predicted peak effect (E(max)AND ) of 64.44 +/- 14.64 and 66.02 +/- 11.51% were achieved at 14.7 +/- 7. 4 and 8.5 +/- 2.2 min after i.m. and i.v. dosing, respectively. Peak a nalgesia appeared much later than peak plasma concentration, but simul taneously with peak CSF level both after i.m. and i.v. dosing. An obvi ous hysteresis was demonstrated between plasma concentration and analg esic effect. This study demonstrates that meperidine analgesia can be predicted using a PK-PD model, but not by PK data alone. Both i.m. and i.v. administration routes were evaluated kinetically and dynamically .