Characterization of Pharmacodynamic Recession Slopes for Direct and Indirect Response Models

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Abstract
Direct pharmacologic effects are known to recede over time with largely linear slopes (Levy's k · m product, J. Pharm. Sci. 53:342, 1964) and indirect responses have similar behavior. Pharmacodynamic slope properties were examined mathematically for the Hill function with monoexponential drug disposition and simulations were carried out for other pharmacokinetic functions. Both types of pharmacodynamic profiles exhibit a single terminal inflection point (fp) when drug concentrations exceed the EC50(that concentration causing one-half maximum effect, Emax). For direct effects it was found that Cfp(the drug concentration at fp) =EC50, the determinants of inflection time were identified, and Slopefp = −λzγEmax/4 where λzis the terminal disposition slope and γ is the Hill coefficient. These characteristics were explored for the four basic indirect response models which also exhibit recession profiles with slight sigmoidity and a single terminal inflection point at higher doses. The drug concentration at inflection Cfpis ≤IC50or SC50(drug concentrations causing half-maximal inhibition or stimulation), while the inflection response (Rfp) attains constant values at larger doses. Indirect Response Models I, III, and IV have nearly linear return slopes for a wide range of doses which are governed by the disposition slope λzof the drug, loss constant koutof the response, maximum inhibition (Imax) or stimulation (Smax) factors, and a unique fractional constant (01). Model II exhibits more complex behavior with recession slopes which are less likely to be parallel for various doses. Most indirect responses are expected to show nearly linear recession slopes which are parallel for moderate to large doses and mainly governed by an identical combination of pharmacokinetic (λz), system (kout), and dynamic capacity factors (Imaxor Smax).

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