Bart de Laat1, Jocelyn Hoye1, Heather Liu2, Evan D Morris3,4,5. 1. Department of Radiology and Biomedical Imaging, Yale University, New Haven, CT, USA. 2. Department of Biomedical Engineering, Yale University, CT, New Haven, USA. 3. Department of Radiology and Biomedical Imaging, Yale University, New Haven, CT, USA. evan.morris@yale.edu. 4. Department of Psychiatry, Yale University, New Haven, CT, USA. evan.morris@yale.edu. 5. Department of Biomedical Engineering, Yale University, CT, New Haven, USA. evan.morris@yale.edu.
Abstract
PURPOSE: We recently introduced voxel-level images of drug occupancy from PET via our "Lassen plot filter." Occupancy images revealed clear dependence of 11C-flumazenil displacement on dose of GABAa inhibitor, CVL-865, but with different scales in different brain regions. We hypothesized that regions requiring higher drug concentrations to achieve desired occupancy would have higher EC50 values. We introduce an "EC50 image" from human data to evaluate this hypothesis. METHODS: Five healthy subjects were scanned with the nonselective GABAa tracer, 11C-flumazenil, before and (twice) after administration of CVL-865. We created ten occupancy images and applied an Emax model locally to create one EC50 image. We also performed simulations to confirm our observations of regional variation in EC50 and to identify the main source of variability in EC50. RESULTS: As expected, the EC50 image revealed spatial variation in apparent drug affinity. High EC50 was found in areas of low occupancy for a given drug dose. Simulations demonstrated that sampling from an inadequate range of plasma drug concentrations could impair precision. CONCLUSION: Our results argue for (a) confidence in the ability of the EC50 images to identify regional differences and (b) a need to tailor the range of drug doses in an occupancy study to regularize the precision of the EC50 throughout the brain. The EC50 image could add value to early-phase drug development by identifying regional variation in affinity that might impact therapy or safety and by guiding dose selection for later-phase trials.
PURPOSE: We recently introduced voxel-level images of drug occupancy from PET via our "Lassen plot filter." Occupancy images revealed clear dependence of 11C-flumazenil displacement on dose of GABAa inhibitor, CVL-865, but with different scales in different brain regions. We hypothesized that regions requiring higher drug concentrations to achieve desired occupancy would have higher EC50 values. We introduce an "EC50 image" from human data to evaluate this hypothesis. METHODS: Five healthy subjects were scanned with the nonselective GABAa tracer, 11C-flumazenil, before and (twice) after administration of CVL-865. We created ten occupancy images and applied an Emax model locally to create one EC50 image. We also performed simulations to confirm our observations of regional variation in EC50 and to identify the main source of variability in EC50. RESULTS: As expected, the EC50 image revealed spatial variation in apparent drug affinity. High EC50 was found in areas of low occupancy for a given drug dose. Simulations demonstrated that sampling from an inadequate range of plasma drug concentrations could impair precision. CONCLUSION: Our results argue for (a) confidence in the ability of the EC50 images to identify regional differences and (b) a need to tailor the range of drug doses in an occupancy study to regularize the precision of the EC50 throughout the brain. The EC50 image could add value to early-phase drug development by identifying regional variation in affinity that might impact therapy or safety and by guiding dose selection for later-phase trials.
Authors: K S Lim; J S Kwon; I-J Jang; J M Jeong; J S Lee; H W Kim; W J Kang; J-R Kim; J-Y Cho; E Kim; S Y Yoo; S-G Shin; K-S Yu Journal: Clin Pharmacol Ther Date: 2007-02 Impact factor: 6.875
Authors: N A Lassen; P A Bartenstein; A A Lammertsma; M C Prevett; D R Turton; S K Luthra; S Osman; P M Bloomfield; T Jones; P N Patsalos Journal: J Cereb Blood Flow Metab Date: 1995-01 Impact factor: 6.200
Authors: S Ashworth; A Berges; E A Rabiner; A A Wilson; R A Comley; R Y K Lai; R Boardley; G Searle; R N Gunn; M Laruelle; V J Cunningham Journal: Br J Pharmacol Date: 2014-03 Impact factor: 8.739
Authors: Patricia Di Ciano; Esmaeil Mansouri; Junchao Tong; Alan A Wilson; Sylvain Houle; Isabelle Boileau; Thierry Duvauchelle; Philippe Robert; Jean Charles Schwartz; Bernard Le Foll Journal: Neuropsychopharmacology Date: 2018-11-30 Impact factor: 7.853
Authors: J Hirvonen; M Kailajärvi; T Haltia; S Koskimies; K Någren; P Virsu; V Oikonen; H Sipilä; P Ruokoniemi; K Virtanen; M Scheinin; J O Rinne Journal: Clin Pharmacol Ther Date: 2009-01-07 Impact factor: 6.875