ACD856, a novel positive allosteric modulator of Trk receptors, single ascending doses in healthy subjects: Safety and pharmacokinetics.
Purpose: AlzeCure Pharma AB is developing novel positive allosteric modulators of Trk-receptors for treatment of Alzheimer's disease, depression, other psychiatric conditions and other disorders where cognition is impaired. The preceding candidate drug ACD855 was shown to have a too long half-life i...
| Publicado en: | European Journal of Clinical Pharmacology Vol. 80; no. 5; pp. 717 - 728 |
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| Autores principales: | , , , , , , |
| Formato: | research tables/charts randomized controlled trial Journal Article |
| Publicado: |
Springer Nature
May2024
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| Acceso en línea: | Ver este registro en EBSCOhost |
| fields | @attributes: recordID: 1 pdfLink: plink: https://search.ebscohost.com/login.aspx?direct=true&db=ccm&AN=176497546&site=ehost-live header: @attributes: shortDbName: ccm uiTerm: 176497546 longDbName: CINAHL Complete uiTag: AN controlInfo: bkinfo: dissinfo: jinfo: jid: 00316970 NP9 jtl: European Journal of Clinical Pharmacology issn: 00316970 maglogo: N pubinfo: dt: May2024 vid: 80 iid: 5 pid: 237 pub: Springer Nature place: New York, New York artinfo: ui: 176497546 175431209 176497546 176497546 10.1007/s00228-024-03645-1 176497546 ppf: 717 ppct: 11 formats: fmt: – @attributes: type: T – @attributes: type: P tig: atl: ACD856, a novel positive allosteric modulator of Trk receptors, single ascending doses in healthy subjects: Safety and pharmacokinetics. aug: au: Nilsson, Boel Bylund, Johan Halldin, Magnus M. Rother, Matthias Rein-Hedin, Erik Önnestam, Kristin Segerdahl, Märta affil: https://ror.org/02agf1x24 AlzeCure Pharma AB, Hälsovägen 7, SE-141 57, Huddinge, Sweden sug: subj: Patient Safety Biochemical Phenomena Administration, Oral Alzheimer's Disease Drug Therapy Depression Drug Therapy Administration, Intravenous Receptors, Cell Surface Pharmacokinetics Human Randomized Controlled Trials Random Assignment Double-Blind Studies Male Adult Biological Availability Drug Tolerance Time Factors Adult: 19-44 years Male ab: Purpose: AlzeCure Pharma AB is developing novel positive allosteric modulators of Trk-receptors for treatment of Alzheimer's disease, depression, other psychiatric conditions and other disorders where cognition is impaired. The preceding candidate drug ACD855 was shown to have a too long half-life in humans to allow further development. To de-risk the development of the follow-up compound ACD856, the oral single ascending dose study of ACD856 in humans was preceded by an intravenous microdose study, assessing the elimination half-life in plasma. Methods: A phase 0 study with a microdose of ACD856 (0.100 mg), was conducted in six healthy male subjects all receiving ACD856. Sequentially, a randomized, placebo-controlled, double-blind Phase I single ascending oral dose study (1 – 150 mg) was conducted, including 56 healthy subjects. Both studies assessed the safety and tolerability, as well as the PK properties of ACD856 after single dose intravenous and oral administration. Results: ACD856 was well tolerated with no treatment emergent, or dose related adverse events or other safety assessments. In the microdose study, ACD856 exhibited a bi-exponential plasma decline, low distribution volume, low plasma clearance with a half-life of approximately 20 hours. Orally, ACD856 exhibited rapid absorption, an almost complete bioavailability and a dose proportional increase in exposure. While the Cmax was lowered and delayed by food intake, the effect on plasma half-life and the overall bioavailability was low. No renal elimination of ACD856 was detected. Conclusion: The prediction proved accurate demonstrating the value of conducting a microdose study prior to ascending dose studies. Trial registration: NCT05783830 March 24, 2023 (microdose study, retrospectively registered) and NCT05077631 October 14, 2021 (single ascending dose study). pubtype: Academic Journal doctype: research tables/charts randomized controlled trial Journal Article ougenre: Article language: English refInfo: holdings: @attributes: islocal: N |
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