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Pharmacokinetic and Pharmacodynamic Effects of a γ‐Secretase Modulator, PF ‐06648671, on CSF Amyloid‐β Peptides in Randomized Phase I Studies
Author(s) -
Ahn Jae Eun,
Carrieri Charles,
Dela Cruz Fernando,
Fullerton Terence,
HajosKorcsok Eva,
He Ping,
Kantaridis Constantino,
Leurent Claire,
Liu Richann,
Mancuso Jessica,
Mendes da Costa Laure,
Qiu Ruolun
Publication year - 2020
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1002/cpt.1570
Subject(s) - pharmacokinetics , pharmacodynamics , pharmacology , tolerability , adverse effect , medicine , placebo , cerebrospinal fluid , biomarker , chemistry , pathology , biochemistry , alternative medicine
γ‐Secretase modulators ( GSM s) represent a promising therapy for Alzheimer's disease by reducing pathogenic amyloid‐β (Aβ) peptide production. Three phase I studies ( NCT 02316756, NCT 02407353, and NCT 02440100) investigated the safety/tolerability, pharmacokinetics ( PK s), and pharmacodynamics ( PD s) of the oral GSM , PF ‐06648671. A PK/PD indirect‐response model was developed (using biomarker data) to simultaneously characterize differential effects of PF ‐06648671 on multiple Aβ species in cerebrospinal fluid ( CSF ). Healthy subjects ( n = 120) received single doses or multiple‐ascending doses of PF ‐06648671/placebo for 14 days. No serious adverse events occurred; severe adverse eventswere 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 PK/PD model well described the tendency of observed CSF Aβ data and the steady‐state effects of PF ‐06648671, supporting its use for predicting central Aβ effects and optimal dose selection for GSM s in future trials.