Pharmacokinetic-pharmacodynamic modeling of tolmetin antinociceptive effect in the rat using an indirect response model: A population approach

The relationship between the pharmacokinetics and the antinociceptive effec t of tolmetin was characterized by an indirect model using a population app roach. Animals received an intra-articular injection of uric acid in the ri ght hindlimb to induce its dysfunction. Once dysfunction was complete, rats received an oral tolmetin dose of 1, 3.2, 10, 31.6, 56.2, or 100 mg/kg and antinociceptive effect and blood tolmetin concentration were simultaneousl y evaluated. tolmerin produced a dose-dependent recovery of functionality, which was not directly related to blood concentration. An inhibitory indire ct response model was used based on these response patterns and the fact th at tolmetin reduced nociception by inhibiting prostaglandin synthesis. Phar macokinetic (PK) and pharmacodynamic (PD) data were simultaneously fitted u sing nonlinear mixed effects modeling (NONMEM) to the one-compartment model and indirect response model. The individual time courses of the response w ere described using Bayesian analysis with population parameters as a prior i estimates. There was good agreement between the predicted and observed da ta. Population analysis yielded a maximal inhibition of the nociceptive res ponse of 76%; and an IC50 of 9.22 mu g/ml. This IC50 is similar to that for tolmetin-induced postaglandin synthesis inhibition in vitro (3.0 mu g/ml). The present results demonstrate that mechanism-based PK-PD analysis using a population approach is useful for quantitating individual responses as,we ll us reflecting the actual mechanism of action of a given drug in vivo.