Pharmacokinetic-pharmacodynamic modeling of the electroencephalogram effects of scopolamine in healthy volunteers

Scopolamine is a muscarinic receptor antagonist commonly used as a pharmaco logical model substance based on the "cholinergic hypothesis" of memory los s in senile dem en tia of the Alzheimer type. The objective of the study wa s to relate pharmacodynamic electroencephalogram (EEG) changes and scopolam ine serum concentration using pharmacokinetic-pharmacodynamic (PK-PD) model ing techniques. This was a randomized, three-way crossover, open-label stud y involving 10 healthy nonsmoking young male volunteers who received either scopolamine 0.5 mg as an intravenous (nr) infusion over 15 minutes or an i ntramuscular (IM) injection or a placebo. The pharmacodynamic EEG measure c onsists of the total power in delta, theta, alpha, and beta bands over fron tal, central, and occipital brain areas. The values of the pharmacokinetic parameters of scopolamine after IV infusion were clearance (CL) 205 +/- 36. 6 L/h, volume of distribution (Vd) 363 +/- 66.7 L, distribution half-life ( t(1/2 alpha)) 2.9 +/- 0.67 min, and terminal half-life (t(1/2 beta)) 105.4 +/- 9.94 min (mean +/- SEM). Mean peak serum concentrations (C-max) were 4. 66 and 0.96 ng/ml after N and IM administration, respectively (p < 0.05). T he area under the serum concentration versus time curve (AUC) after IM admi nistration (81.27 +/- 11.21 ng/ml/min) was significantly lower compared to the value after IV infusion (157.28 +/- 30.86 ng/ml/min) (mean +/- SEM, p < 0.05). Absolute bioavailability of scopolamine after IM injection was 57% +/- 0.08% (mean +/- SEM). After both IV and IM administration, scopolamine induced a decrease in EEG alpha power (7.50-11.25 Hz) over frontal, central , and occipital brain areas compared to placebo (p < 0.05). The individual concentration-EEG effect relationships determined after N infusion of scopo lamine were successfully characterized by a sigmoidal E-max model. The aver aged values of the pharmacodynamic parameters were E-0 = 0.58 <mu>V-2, E-ma x = 0.29 muV(2), EC50 = 0.60 ng/ml, and gamma = 1.17. No time delay between serum concentrations and changes in alpha power was observed, indicating a rapid equilibration between serum and effect site. The results provide the first demonstration of a direct correlation between serum concentrations o f scopolamine and changes in total power in alpha frequency band in healthy volunteers using PK-PD modeling techniques. As regards the effect on the E EG, 0.5 mg of scopolamine administered N appears to be a suitable dose. Jou rnal of Clinical Pharmacology, 2001;41:51-60 (C) 2001 the American College of Clinical Pharmacology.