Institution: | De Haes, Ann M.D.*; Proost, Johannes H. Pharm.D., Ph.D.†; De Baets, Mark H. M.D., Ph.D.‡; Stassen, Maurice H. W. M.Sc.§; Houwertjes, Martin C.∥; Wierda, J. Mark K. H. M.D., Ph.D.# |
Abstract: | Background: In myasthenic patients, the sensitivity for nondepolarizing relaxants is increased and the time course of effect is prolonged due to a reduced number of functional acetylcholine receptors at the neuromuscular junction. The authors investigated both the performance of the link model proposed by Sheiner and a pharmacodynamic-pharmacokinetic model taking into account the number of unbound acetylcholine receptors in myasthenic pigs. Methods: After obtaining the approval of the Animal Experiments Committee of their institution, the authors studied eight myasthenic pigs and eight control pigs. Myasthenia gravis was induced by injecting Torpedo acetylcholine receptors in weeks 1 and 4. On the day of the experiments, the pigs were anesthetized and intubated, and the appropriate muscles and nerves were prepared for the measurements. Rocuronium was administered by infusion to reach 90% twitch height block. Arterial blood was sampled during onset and offset of effect, and the plasma concentration of rocuronium was measured with high-performance liquid chromatography. Plasma concentration-time effect data were analyzed using two different pharmacokinetic-pharmacodynamic models, the link model according to Sheiner and a pharmacokinetic-pharmacodynamic model taking into account the unbound receptor concentration. Muscles were removed after the experiment for laboratory analysis of the acetylcholine receptor concentration. Results: All eight pigs of the myasthenic group developed clinical signs of myasthenia gravis (muscle weakness) and showed increased sensitivity toward rocuronium. Pharmacokinetic modeling revealed no significant differences between myasthenic and control pigs. In pharmacokinetic-pharmacodynamic analysis, visual inspection as well as the Akaike Information Criterion (3,605 vs. 3,769) and the residual SD (3.2 vs. 3.6%) revealed a better fit for the unbound receptor model in myasthenic animals compared to the Sheiner model. Pharmacokinetic-pharmacodynamic analysis with the unbound receptor model demonstrated a decreased EC50 of 0.27 mu]m (ranging from 0.17 to 0.59 mu]m) compared to 2.71 mu]m (ranging from 2.42 to 4.43 mu]m) in control animals. The results of the Sheiner pharmacokinetic-pharmacodynamic analysis were in the same range. Both the laboratory analysis and pharmacokinetic-pharmacodynamic modeling showed a decrease in receptor concentration of more than 75%. |