TY  - BOOK
AU  - Goldwater, Ronald
TI  - AZD3293: Pharmacokinetic and Pharmacodynamic Effects in Healthy Subjects and Patients with Alzheimer's Disease
SN  - 1387-2877
PY  - 2017///
KW  - *Alzheimer Disease/dt [Drug Therapy]
KW  - *Antipsychotic Agents/pk [Pharmacokinetics]
KW  - *Antipsychotic Agents/tu [Therapeutic Use]
KW  - *Imidazoles/pk [Pharmacokinetics]
KW  - *Imidazoles/tu [Therapeutic Use]
KW  - *Spiro Compounds/pk [Pharmacokinetics]
KW  - *Spiro Compounds/tu [Therapeutic Use]
KW  - Adolescent
KW  - Adult
KW  - Age Factors
KW  - Aged
KW  - Aged, 80 and over
KW  - Amyloid beta-Peptides/bl [Blood]
KW  - Amyloid beta-Peptides/cf [Cerebrospinal Fluid]
KW  - Cross-Over Studies
KW  - Dose-Response Relationship, Drug
KW  - Double-Blind Method
KW  - Drug Administration Schedule
KW  - Female
KW  - Follow-Up Studies
KW  - Food
KW  - Healthy Volunteers
KW  - Humans
KW  - Male
KW  - Middle Aged
KW  - Neurologic Examination
KW  - Peptide Fragments/bl [Blood]
KW  - Peptide Fragments/cf [Cerebrospinal Fluid]
KW  - Time Factors
KW  - Young Adult
KW  - MedStar Harbor Hospital
KW  - Clinical Trial, Phase I
KW  - Journal Article
KW  - Randomized Controlled Trial
N2  - AZD3293 (LY3314814) is a promising new potentially disease-modifying BACE1 (beta-secretase) inhibitor in Phase III clinical development for the treatment of Alzheimer's disease. Reported here are the first two Phase I studies: (1) a single ascending dose study evaluating doses of 1-750 mg with a food-effect component (n = 72), and (2) a 2-week multiple ascending dose study evaluating doses of 15 or 50 mg once daily (QD) or 70 mg once weekly (QW) in elderly subjects (Part 1, n = 31), and 15, 50, or 150 mg QD in patients with mild to moderate Alzheimer's disease (Part 2, n = 16). AZD3293 was generally well tolerated up to the highest doses given. No notable food effects were observed. PK following multiple doses (Part 2) were tmax of 1 to 3 h and mean t1/2 of 16 to 21 h across the 15 to 150 mg dose range. For single doses of >=5 mg, a >=70% reduction was observed in mean plasma Abeta40 and Abeta42 concentrations, with prolonged suppression for up to 3 weeks at the highest dose level studied. Following multiple doses, robust reductions in plasma (>=64% at 15 mg and >=78% at >=50 mg) and cerebrospinal fluid (>=51% at 15 mg and >=76% at >=50 mg) Abeta peptides were seen, including prolonged suppression even with a QW dosing regimen. AZD3293 is the only BACE1 inhibitor for which prolonged suppression of plasma Abeta with a QW dosing schedule has been reported. Two Phase III studies of AZD3293 (AMARANTH, NCT02245737; and DAYBREAK-ALZ, NCT02783573) are now ongoing
UR  - http://dx.doi.org/10.3233/JAD-160701
ER  -