Target Reserve and Turnover Parameters Determine Rightward Shift of Enalaprilat Potency From its Binding Affinity to the Angiotensin Converting Enzyme.

• A mechanism-based hybrid model, coupling target-mediated drug disposition and a minimal model of the renin-angiotensin system, was developed to characterize the pharmacokinetic and pharmacodynamic properties of enalaprilat, administered as the prodrug enalapril, in humans. • Model-based simulations of the final model predicted about a 6- to 7-fold shift in the enalaprilat ex vivo potency from its in vivo binding affinity, which is consistent with both observations and theoretical expectations of pharmacological antagonists that exhibit target-mediated drug disposition (TMDD). • Empirical functions based on operational models of agonism/antagonism were also derived that similarly suggest a role of drug, angiotensin, and total receptor concentration in the shift in enalaprilat ex vivo potency from in vivo binding affinity. Drug effects are often assumed to be directly proportional to the fraction of occupied targets. However, for a number of antagonists that exhibit target-mediated drug disposition (TMDD), such as angiotensin-converting enzyme (ACE) inhibitors, drug binding to the target at low concentrations may be significant enough to influence pharmacokinetics but insufficient to elicit a drug response (i.e., differences in drug-target binding affinity and potency). In this study, a pharmacokinetic/pharmacodynamic model for enalaprilat was developed in humans to provide a theoretical framework for assessing the relationship between ex vivo drug potency (IC 50) and in vivo target - binding affinity (K D). The model includes competitive binding of angiotensin I and enalaprilat to ACE and accounts for the circulating target pool. Data were obtained from the literature, and model fitting and parameter estimation were conducted using maximum likelihood in ADAPT5. The model adequately characterized time-courses of enalaprilat concentrations and four biomarkers in the renin-angiotensin system and provided estimates for in vivo K D (0.646 nM) and system-specific parameters, such as total target density (32.0 nM) and fraction of circulating target (19.8%), which were in agreement with previous reports. Model simulations were used to predict the concentration-effect curve of enalaprilat, revealing a 6.3-fold increase in IC 50 from K D. Additional simulations demonstrated that target reserve and degradation parameters are key factors determining the extent of shift of enalaprilat ex vivo potency from its in vivo binding affinity. This may be a common phenomenon for drugs exhibiting TMDD and has implications for translating binding affinity to potency in drug development. [ABSTRACT FROM AUTHOR]