Physiologically Based Pharmacokinetic and Pharmacodynamic Modeling of Diazepam: Unbound Interstitial Brain Concentrations Correspond to Clinical End Points.

Benzodiazepines induce a series of clinical effects by modulating subtypes of γ-aminobutyric acid type A receptors in the central nervous system. The brain concentration-time profiles of diazepam that correspond to these effects are unknown, but can be estimated with physiologically based pharmacokinetic (PBPK) modeling. In this study, a PBPK model for the 1,4-benzodiazepines diazepam and nordiazepam was developed from plasma concentration-time courses with PK-Sim software to predict brain concentrations. The PBPK model simulations accurately parallel plasma concentrations from both an internal model training data set and an external data set for both intravenous and peroral diazepam administrations. It was determined that the unbound interstitial brain concentration-time profiles correlated with diazepam pharmacodynamic end points. With a 30-mg intravenous diazepam dose, the peak unbound interstitial brain concentration from this model is 160 nM at 2 minutes and 28.9 nM at 120 minutes. Peak potentiation of recombinant γ-aminobutyric acid type A receptors composed of α1β2γ2s, α2β2γ2s, and α5β2γ2s subunit combinations that are involved in diazepam clinical endpoints is 108%, 139%, and 186%, respectively, with this intravenous dose. With 10-mg peroral administrations of diazepam delivered every 24 hours, steady-state peak and trough unbound interstitial brain diazepam concentrations are 22.3 ± 7.5 and 9.3 ± 3.5 nM. Nordiazepam unbound interstitial brain concentration is 36.1 nM at equilibrium with this diazepam dosing schedule. Pharmacodynamic models coupled to the diazepam unbound interstitial brain concentrations from the PBPK analysis account for electroencephalographic drug effect, change in 13- to 30-Hz electroencephalographic activity, amnesia incidence, and sedation score time courses from human subjects.