Designing drug occupancy studies with PET neuroimaging: Sample size, occupancy ranges and analytical methods
Gjertrud Louise Laurell,
Pontus Plavén-Sigray,
Claus Svarer,
R. Todd Ogden,
Gitte Moos Knudsen,
Martin Schain
Affiliations
Gjertrud Louise Laurell
Neurobiology Research Unit, Copenhagen University Hospital Rigshospitalet, 6-8 Inge Lehmanns Vej, Rigshospitalet, Copenhagen DK-2100, Denmark; Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Corresponding author at: Neurobiology Research Unit, 6-8 Inge Lehmanns Vej, Rigshospitalet, DK-2100, Copenhagen, Denmark.
Pontus Plavén-Sigray
Neurobiology Research Unit, Copenhagen University Hospital Rigshospitalet, 6-8 Inge Lehmanns Vej, Rigshospitalet, Copenhagen DK-2100, Denmark
Claus Svarer
Neurobiology Research Unit, Copenhagen University Hospital Rigshospitalet, 6-8 Inge Lehmanns Vej, Rigshospitalet, Copenhagen DK-2100, Denmark
R. Todd Ogden
Department of Biostatistics, Columbia University, New York, NY, United States; Molecular Imaging and Neuropathology Area, New York State Psychiatric Institute, New York, NY, United States
Gitte Moos Knudsen
Neurobiology Research Unit, Copenhagen University Hospital Rigshospitalet, 6-8 Inge Lehmanns Vej, Rigshospitalet, Copenhagen DK-2100, Denmark; Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
Martin Schain
Neurobiology Research Unit, Copenhagen University Hospital Rigshospitalet, 6-8 Inge Lehmanns Vej, Rigshospitalet, Copenhagen DK-2100, Denmark; Antaros Medical AB, Mölndal, Sweden
Molecular neuroimaging is today considered essential for evaluation of novel CNS drugs; it is used to quantify blood-brain barrier permeability, verify interaction with key target and determine the drug dose resulting in 50% occupancy, IC50. In spite of this, there has been limited data available to inform on how to optimize study designs.Through simulations, we here evaluate how IC50 estimation is affected by the (i) range of drug doses administered, (ii) number of subjects included, and (iii) level of noise in the plasma drug concentration measurements. Receptor occupancy is determined from PET distribution volumes using two different methods: the Lassen plot and Likelihood estimation of occupancy (LEO). We also introduce and evaluate a new likelihood-based estimator for direct estimation of IC50 from PET distribution volumes.For estimation of IC50, we find very limited added benefit in scanning individuals who are given drug doses corresponding to less than 40% receptor occupancy. In the range of typical PET sample sizes (5–20 subjects) each extra individual clearly reduces the error of the IC50 estimate.In all simulations, likelihood-based methods gave more precise IC50 estimates than the Lassen plot; four times the number of subjects were required for the Lassen plot to reach the same IC50 precision as LEO.
