Michael B. Bolger (1), Ronald Irwin (2), Lon S. Schneider (3), and Roberta Diaz Brinton (2)
(1) Simulations Plus, Inc., 42505 10th Street West, Lancaster, CA 93534, (2) University of Southern California (USC) School of Pharmacy 1985 Zonal Avenue, PSC-502 Los Angeles, CA 90033, (3) USC Departments of Psychiatry and Neurology, Keck School of Medicine and Gerontology, Andrus School of Gerontology, Los Angeles, CA 90033.
Objectives: 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 3alpha-hydroxy-5alpha-pregnan-20-one (AP-alpha) has been shown to promote neurogenesis in mice in vitro and in vivo [2-3]. In addition, AP-alpha has be shown to restore hippocampal-dependent learning and memory and neural progenitor cell survival in aging 3xTgAD and nonTg 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-alpha [5]. Data from the literature on the pharmacokinetics and pharmacodynamics of AP-alpha in mice and humans were compared to PBPK/PD models built using GastroPlus 8.0(TM) (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 indirect-link effect compartment PD model [6] was parameterized using data from iv administration of AP-alpha to healthy women, and measurements of the % change in saccadic eye movement [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-alpha 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.
References: [1] Carter, R. B., P. L. Wood, et al. (1997). “Characterization of the anticonvulsant properties of ganaxolone (CCD 1042), a selective, high-affinity, steroid modulator of the GABAa receptor.” J Pharmacol Exp Ther 280(3): 1284-1295.
[2]Brinton, R. D. and J. M. Wang (2006). “Preclinical analyses of the therapeutic potential of allopregnanolone to promote neurogenesis in vitro and in vivo in transgenic mouse model of Alzheimer’s disease.” Curr Alzheimer Res 3(1): 11-17.
[3]Wang JM, Singh C, et al., (2010) Allopregnanolone reverses neurogenic and cognitive deficits in mouse model of Alzheimer’s disease Proc. Natl. Acad. Sci . 107(14):6498-503.
[4]Singh, C., L. Liu, et al. (2011). “Allopregnanolone restores hippocampal-dependent learning and memory and neural progenitor survival in aging 3xTgAD and nonTg mice.” Neurobiol Aging.
[5]Bolger, M. B., R. Fraczkiewicz, et al. (2006). In silico surrogates for vivo properties: Profiling for ADME and toxicological behaviour. Exploiting Chemical Diversity for Drug Discovery. P. A. B. a. M. Entzeroth. London, Royal Society of Chemistry: 364-381.
[6]Jusko, W. J. and H. C. Ko (1994). “Physiologic indirect response models characterize diverse types of pharmacodynamic effects.” Clin Pharmacol Ther 56(4): 406-419.
[7]Timby, E., M. Balgard, et al. (2006). “Pharmacokinetic and behavioral effects of allopregnanolone in healthy women.” Psychopharmacology (Berl) 186(3): 414-424.
Reference: PAGE 21 (2012) Abstr 2596 [www.page-meeting.org/?abstract=2596]
Poster: Absorption and Physiology-Based PK