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Pharmacokinetics and safety profile of intramuscular administration of allopregnanolone in patients with Alzheimer’s disease
Author(s) -
Hernandez Gerson D.,
Lopez Claudia M.,
Wang Yiwei,
Rodgers Kathleen E.,
Schneider Lon,
Brinton Roberta Diaz
Publication year - 2020
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1002/alz.046223
Subject(s) - tolerability , pharmacokinetics , medicine , dosing , area under the curve , allopregnanolone , intramuscular injection , regimen , clinical endpoint , adverse effect , pharmacology , anesthesia , urology , clinical trial , gastroenterology , neuroactive steroid , receptor , gabaa receptor
Background Allopregnanolone (Allo) is a novel regenerative therapeutic that also reduces the burden of Alzheimer’s disease (AD) pathology. We have previously established safety, tolerability and a pharmacokinetic profile of Allo administered intravenously in AD patients. In this phase 1b trial, we assess the safety, tolerability and pharmacokinetics of Allo administered via an intramuscular injection in patients with AD. Method An open label, multiple ascending dose, phase 1b clinical trial was conducted in patients ranging from mild cognitive impairment due to AD to moderate AD. Men and women age ≥ 55 years, with a MMSE score ≥10 were recruited to the study. Patients had previously participated in the phase 1 study of Allo administered IV. Participants received weekly intramuscular injections with a dose escalation regimen of 4, 8, 12 and 16mg of Allo. Blood was collected before the injection and after at the following timepoints: 5, 15, 30, 45 minutes; 1, 2, and 4 hours. Primary outcomes included safety and tolerability parameters. Secondary endpoints included PK parameters: t max (time to reach maximum plasma concentration), C max (maximum plasma concentration), AUC 0‐last (area under the plasma concentration‐time curve from time zero to time of the last measured concentration above the limit of quantification), AUC 0‐inf (area under the plasma concentration‐time curve from zero to infinity), t ½ (terminal elimination half‐life).This is part of an IV to IM bridging study to determine the IM formulation dose that is equivalent to the IV Allo dosing (Clinicaltrials.gov: NCT03748303). Result A total of 6 participants have completed the pharmacokinetic assessment. Injection was well tolerated and did not elicit adverse events. Pharmacokinetic profile indicates direct rank order and near dose proportionality for both T max and AUC inf. Second group dosing and study procedures are currently underway. Conclusion Intramuscular administration of allopregnanolone was well tolerated, and did not elicit adverse effects in the initial cohort. Pharmacokinetic profile indicates direct rank order and near dose proportionality for both T max and AUC inf. Acknowledgments: Alzheimer’s Association Part The Cloud, Alzheimer’s Drug Discovery Foundation.