Pharmacokinetics and safety profile of intramuscular administration of allopregnanolone in patients with Alzheimer’s disease

Abstract

AbstractBackgroundAllopregnanolone (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.MethodAn 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: tmax (time to reach maximum plasma concentration), Cmax (maximum plasma concentration), AUC0‐last (area under the plasma concentration‐time curve from time zero to time of the last measured concentration above the limit of quantification), AUC0‐inf (area under the plasma concentration‐time curve from zero to infinity), t½ (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).ResultA 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 Tmax and AUCinf. Second group dosing and study procedures are currently underway.ConclusionIntramuscular 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 Tmax and AUCinf. Acknowledgments: Alzheimer’s Association Part The Cloud, Alzheimer’s Drug Discovery Foundation.