Pharmacokinetic and pharmacodynamic effects of a γ-secretase modulator, PF-06648671, on CSF amyloid-β peptides in randomized Phase 1 studies.
Clin Pharmacol Ther. 2019 Jul 17;:
Authors: Eun Ahn J, Carrieri C, Dela Cruz F, Fullerton T, Hajos-Korcsok E, He P, Kantaridis C, Leurent C, Liu R, Mancuso J, Mendes da Costa L, Qiu R
γ-Secretase modulators (GSMs) represent a promising therapy for Alzheimer’s disease by reducing pathogenic amyloid-β (Aβ) peptide production. Three Phase 1 studies (NCT02316756, NCT02407353, NCT02440100) investigated the safety/tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of the oral GSM, PF-06648671. A PKPD indirect-response model was developed (using biomarker data) to simultaneously characterize differential effects of PF-6648671 on multiple Aβ species in cerebrospinal fluid (CSF). Healthy subjects (n=120) received single- or multiple-ascending doses of PF-06648671/placebo for 14 days. No serious adverse events occurred; severe adverse events were deemed not drug-related. PF-06648671 decreased Aβ42 and Aβ40 concentrations in CSF, with greater effects on Aβ42, and increased Aβ37 and Aβ38 levels, particularly Aβ37. No significant change in total Aβ was observed. The PKPD model well described the tendency of observed CSF Aβ data and steady-state effects of PF-06648671, supporting its use for predicting central Aβ effects and optimal dose selection for GSMs in future trials. This article is protected by copyright. All rights reserved.
PMID: 31314925 [PubMed – as supplied by publisher]