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GastroPlus PBPK/PD Model Applied to Estimating Dose for an Elderly Population in an Alzheimer's Disease Clinical Trial

Certain neurosteroid metabolites of progesterone are known to be positive allosteric modulators of the GABAa receptor and have application as anticonvulsant, anxiolytic, and sedative hypnotic agents [1]. More recently 3α-hydroxy-5α-pregnan-20one (AP-α) has been shown to promote neurogenesis in mice in vitro and in vivo [2-3]. In addition, AP-α has been shown to restore hippocampal-dependent learning and memory and neural progenitor cell survival in aging 3xTgAD and non-Tg mice [4]. Our objective was to explore the application of mechanistic absorption PBPK/PD modeling and simulation to the translation of basic science discoveries and preclinical data in support of developmental human clinical trials. Methods: ADMET Predictor(TM) (Simulations Plus, Inc.) was used to estimate the biopharmaceutical properties of AP-α [5]. Data from the literature on the pharmacokinetics and pharmacodynamics of AP-α in mice and humans were compared to PBPK/PD models built using GastroPlus 8.0™ (Simulations Plus, Inc.) to establish a prediction for a dosing regimen and expected human exposure in support of a developmental clinical trial in Alzheimer’s patients. An indirectlink effect compartment PD model [6] was parameterized using data from iv administration of AP-α to healthy women, and measurements of the % change in saccadic eye velocity [7]. Results: The mouse PBPK model was able to explain the observed plasma concentrations at three doses (1, 10, and 20 mg/Kg) and the observed cortex level following the 1 mg/Kg dose. Human clinical trial data for intravenous doses of AP-α linked to a pharmacodynamic model of saccadic eye movement were successfully modeled. Finally, an intravenous dosing regimen for an elderly population was proposed to achieve similar brain concentrations as observed in the mouse preclinical studies but to avoid the sedation inducing concentrations observed in the previous human clinical trials. Conclusions: The validated PBPK/PD model for allopregnanolone supplied prospective plasma and brain concentrations for iv dosing in an elderly population. Final results from the developmental clinical trial will be compared to this prediction when the studies are complete. GastroPlus can be used for translational research and facilitates multidisciplinary collaborations.