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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.

Pharmacokinetic and Pharmacodynamic Effects of a γ‐Secretase Modulator, PF ‐06648671, on CSF Amyloid‐β Peptides in Randomized Phase I Studies