Allopregnanolone Preclinical Acute Pharmacokinetic and Pharmacodynamic Studies to Predict Tolerability and Efficacy for Alzheimer’s Disease

Abstract

To develop allopregnanolone as a therapeutic for Alzheimer’s disease, we investigated multiple formulations and routes of administration in translationally relevant animal models of both sexes. Subcutaneous, topical (transdermal and intranasal), intramuscular, and intravenous allopregnanolone were bolus-administered. Pharmacokinetic analyses of intravenous allopregnanolone in rabbit and mouse indicated that peak plasma and brain levels (3-fold brain/plasma ratios) at 5min were sufficient to activate neuroregenerative responses at sub-sedative doses. Slow-release subcutaneous suspension of allopregnanolone displayed 5-fold brain/plasma ratio at Cmax at 30min. At therapeutic doses by either subcutaneous or intravenous routes, allopregnanolone mouse plasma levels ranged between 34-51ng/ml by 30min, comparable to published endogenous human level in the third trimester of pregnancy. Exposure to subcutaneous, topical, intramuscular, and intravenous allopregnanolone, at safe and tolerable doses, increased hippocampal markers of neurogenesis including BrdU and PCNA in young 3xTgAD and aged wildtype mice. Intravenous allopregnanolone transiently and robustly phosphorylated CREB within 5min and increased levels of neuronal differentiation transcription factor NeuroD within 4h. Neurogenic efficacy was achieved with allopregnanolone brain exposure of 300-500hr*ng/g. Formulations were tested to determine the no observable adverse effect level (NOAEL) and maximally tolerated doses (MTD) in male and female rats by sedation behavior time course. Sex differences were apparent, males exhibited ≥40% more sedation time compared to females. Allopregnanolone formulated in sulfobutyl-ether-beta-cyclodextrin at optimized complexation ratio maximized allopregnanolone delivery and neurogenic efficacy. To establish the NOAEL and MTD for Allo-induced sedation using a once-per-week intravenous regenerative treatment regimen: In female rats the NOAEL was 0.5mg/kg and MTD 2mg/kg. The predicted MTD in human female is 0.37mg/kg. In male rats the NOAEL and MTD were less than those determined for female. Outcomes of these PK/PD studies predict a safe and efficacious dose range for initial clinical trials of allopregnanolone for Alzheimer’s disease. These findings have translational relevance to multiple neurodegenerative conditions.

5α-reduced progestogens ameliorate mood-related behavioral pathology, neurotoxicity, and microgliosis associated with exposure to HIV-1 Tat

“…Higher concentrations may directly activate GABA A receptors (Lambert et al, 1990) and were considered non-optimal. Moreover, others have utilized the present dosing regimen to determine potential efficacy for clinical trials aimed at assessing AlloP-protection over Alzheimer’s related cognitive impairment (Irwin & Brinton, 2014; Irwin et al, 2015). …”

Clinical Potential of Neurosteroids for CNS Disorders

“…Although the complex etiology of this disease has thus far thwarted many therapeutic approaches, recent reports have demonstrated the therapeutic potential of AP in this setting via a neurodegenerative mechanism [110, 111]. In the murine AD model, 3xTgAD, AP achieved successful restoration of normal cognitive function concurrent with a reduction in molecular markers of disease.…”

“…AP meets several criteria for suitability as a therapeutic agent, including low molecular weight, minimal hydrogen bond formation, favorable pharmacokinetics, and therapeutic efficacy at a sub-sedative dose. Furthermore, extensive analysis regarding route of administration, pharmacokinetics, neurogenic efficacy, tolerability, and dosing have already been performed in preparation for clinical trials, with broader translational implications for AP [110]. …”

Cyclodextrins as Emerging Therapeutic Tools in the Treatment of Cholesterol-Associated Vascular and Neurodegenerative Diseases

“…Cholesterol depletion [11,12] Methyl-β-CD Cholesterol depletion [12] HPβCD Cholesterol depletion [13,[53][54][55][56] Reduces inflammation and lowers atherosclerotic lesion formation, reduces amounts of cholesterol crystals in atherosclerotic plaques [13] Niemann-Pick type C SBE7-β-CD Nasal delivery system for brain targeting, decreases Aβ-induced neurotoxicity in rat hippocampus [73], associated with tacrine/albumin Improved brain delivery and neurogenic drug efficacy [77], coupled with allopregnanolone Table 2. Cont.…”

“…The authors explained this latter disappointing observation in regards to memory improvements induced with curcumin nanoparticles due to the fact that amyloid plaque size is barely correlated with memory loss [126,127]. Lately, HPβCD or SBE7-β-CD associated with the neurosteroid allopregnanolone was shown to greatly improve the delivery and neurogenic efficacy of the drug upon diverse modes of administration (subcutaneous, topical, intramuscular and intravenous) in various animal models (rabbits, rats, mice, the triple transgenic Alzheimer's mouse model 3xTgAD) [77]. Shan and colleagues (2016) recently designed novel spray-dried microspheres prepared with β-CD supplemented with two active compounds: chitosan and phospholipids [74].…”