Method Profile
In vitro permeability, efflux and brain-binding measurements are translated into a brain PBPK model and evaluated against later clinical cerebrospinal-fluid measurements.
Prospective research assessment of fenebrutinib CNS exposure during drug development.
A five-compartment mechanistic brain PBPK model with passive permeability, efflux transport and binding inputs.
Assess the approach using a reference compound with public clinical CSF data, derive empirical scalars, then prospectively predict fenebrutinib CSF concentrations.
Model inputs
In vitro permeability, efflux-transporter activity, brain binding and physiological parameters.
Clinical comparison
Public clinical CSF data for a reference compound and subsequently available fenebrutinib measurements in multiple-sclerosis patients.
Use reference-compound data to assess in vitro-to-in vivo translation, then compare the prospective fenebrutinib forecast with later clinical measurements.
A reference-compound assessment precedes prospective fenebrutinib CSF prediction and a later clinical comparison.
Reference-compound clinical CSF data and later fenebrutinib CSF measurements in patients with multiple sclerosis.
Predicted fenebrutinib CSF concentrations versus measured patient CSF concentrations.
Predictions fell within 1.5-fold of the later measurements.
Genentech researchers combined in vitro permeability, efflux and binding data in a five-compartment brain model. Predictions were within 1.5-fold of cerebrospinal-fluid concentrations measured later in people with multiple sclerosis.
