Allopregnanolone preclinical acute pharmacokinetic and pharmacodynamic studies to predict tolerability and efficacy for Alzheimer's disease.
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 w...
| Main Authors: | , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2015-01-01
|
| Series: | PLoS ONE |
| Online Access: | https://doi.org/10.1371/journal.pone.0128313 |
| _version_ | 1818826231297081344 |
|---|---|
| author | Ronald W Irwin Christine M Solinsky Carlos M Loya Francesco G Salituro Kathleen E Rodgers Gerhard Bauer Michael A Rogawski Roberta Diaz Brinton |
| author_facet | Ronald W Irwin Christine M Solinsky Carlos M Loya Francesco G Salituro Kathleen E Rodgers Gerhard Bauer Michael A Rogawski Roberta Diaz Brinton |
| author_sort | Ronald W Irwin |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-19T00:24:22Z |
| format | Article |
| id | doaj.art-040fc371d0ab4f1ca16b64dd413384d7 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-19T00:24:22Z |
| publishDate | 2015-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-040fc371d0ab4f1ca16b64dd413384d72022-12-21T20:45:20ZengPublic Library of Science (PLoS)PLoS ONE1932-62032015-01-01106e012831310.1371/journal.pone.0128313Allopregnanolone preclinical acute pharmacokinetic and pharmacodynamic studies to predict tolerability and efficacy for Alzheimer's disease.Ronald W IrwinChristine M SolinskyCarlos M LoyaFrancesco G SalituroKathleen E RodgersGerhard BauerMichael A RogawskiRoberta Diaz BrintonTo 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.https://doi.org/10.1371/journal.pone.0128313 |
| spellingShingle | Ronald W Irwin Christine M Solinsky Carlos M Loya Francesco G Salituro Kathleen E Rodgers Gerhard Bauer Michael A Rogawski Roberta Diaz Brinton Allopregnanolone preclinical acute pharmacokinetic and pharmacodynamic studies to predict tolerability and efficacy for Alzheimer's disease. PLoS ONE |
| title | Allopregnanolone preclinical acute pharmacokinetic and pharmacodynamic studies to predict tolerability and efficacy for Alzheimer's disease. |
| title_full | Allopregnanolone preclinical acute pharmacokinetic and pharmacodynamic studies to predict tolerability and efficacy for Alzheimer's disease. |
| title_fullStr | Allopregnanolone preclinical acute pharmacokinetic and pharmacodynamic studies to predict tolerability and efficacy for Alzheimer's disease. |
| title_full_unstemmed | Allopregnanolone preclinical acute pharmacokinetic and pharmacodynamic studies to predict tolerability and efficacy for Alzheimer's disease. |
| title_short | Allopregnanolone preclinical acute pharmacokinetic and pharmacodynamic studies to predict tolerability and efficacy for Alzheimer's disease. |
| title_sort | allopregnanolone preclinical acute pharmacokinetic and pharmacodynamic studies to predict tolerability and efficacy for alzheimer s disease |
| url | https://doi.org/10.1371/journal.pone.0128313 |
| work_keys_str_mv | AT ronaldwirwin allopregnanolonepreclinicalacutepharmacokineticandpharmacodynamicstudiestopredicttolerabilityandefficacyforalzheimersdisease AT christinemsolinsky allopregnanolonepreclinicalacutepharmacokineticandpharmacodynamicstudiestopredicttolerabilityandefficacyforalzheimersdisease AT carlosmloya allopregnanolonepreclinicalacutepharmacokineticandpharmacodynamicstudiestopredicttolerabilityandefficacyforalzheimersdisease AT francescogsalituro allopregnanolonepreclinicalacutepharmacokineticandpharmacodynamicstudiestopredicttolerabilityandefficacyforalzheimersdisease AT kathleenerodgers allopregnanolonepreclinicalacutepharmacokineticandpharmacodynamicstudiestopredicttolerabilityandefficacyforalzheimersdisease AT gerhardbauer allopregnanolonepreclinicalacutepharmacokineticandpharmacodynamicstudiestopredicttolerabilityandefficacyforalzheimersdisease AT michaelarogawski allopregnanolonepreclinicalacutepharmacokineticandpharmacodynamicstudiestopredicttolerabilityandefficacyforalzheimersdisease AT robertadiazbrinton allopregnanolonepreclinicalacutepharmacokineticandpharmacodynamicstudiestopredicttolerabilityandefficacyforalzheimersdisease |