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Positron Emission Tomography: Tool to Study Pharmacokinetics and to Facilitate Drug Development

Understand the role of Positron Emission Tomography (PET) in studying pharmacokinetics and facilitating drug development. Explore PET imaging of receptors, biomarkers for drug efficacy, and PET kinetics. Learn how PET provides insight into drug distribution, metabolism, and receptor density.

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Positron Emission Tomography: Tool to Study Pharmacokinetics and to Facilitate Drug Development

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  1. Positron Emission Tomography: Tool to Study Pharmacokineticsand to Facilitate Drug Development Robert B. Innis, MD, PhD Molecular Imaging Branch National Institute Mental Health

  2. Outline of Talk • PET has high sensitivity and specificity • PET used in therapeutic drug development • Pharmacokinetic modeling of plasma concentration and tissue uptake can measure receptor density • Study drug distribution: block distribution to periphery and increase distribution to brain • Study drug metabolism: inhibit defluorination

  3. Imaging Receptors with PET

  4. Positron Emission Tomography

  5. PET vs. MRI Radionuclide (11C): high sensitivityLigand (raclopride): high selectivityRadioligand [11C]raclopride: high sensitivity & selectivity

  6. Radioligand = Drug + Radioactivity • Drug administered at tracer doses • No pharm effects • Labels <1% receptors • Labeled subset reflects entire population • Radioligand disposed like all drugs • Metabolism & distribution • Radiation exposure

  7. NIH Rodent PET Camera18F bone uptake rat Developed By: Mike Green & Jurgen Seidel

  8. PET: Tool in TherapeuticDrug Development • Determine dose and dosing interval • Identify homogeneous group • Biomarker for drug efficacy

  9. Lazabemide blocks [11C]deprenyl binding to monoamine-oxidase-B (MAO-B) Selegilene is more potent and longer acting than lazabemide

  10. PET: Tool in TherapeuticDrug Development • Determine dose and dosing interval • Identify homogeneous group • Biomarker for drug efficacy

  11. Dopamine Transporter: Located on DA Terminals Removes DA from Synapse

  12. SPECT Imaging of Dopamine Transporter in Caudate and Putamen of Human Brain

  13. Dopamine Transporter SPECT in Parkinson’s Disease: Decreased, asymmetrical, loss in putamen > caudate Healthy Parkinson Stage 1

  14. PET: Tool in TherapeuticDrug Development • Determine dose and dosing interval • Identify homogeneous group • Biomarker for drug efficacy

  15. Serial Dopamine Transporter Imaging in a Parkinson Patient Institute for Neurodegenerative Disorders

  16. PET Imaging of Amyloid: Biomarker for Alzheimer’s Disease

  17. Outline of Talk • PET has high sensitivity and specificity • PET used in therapeutic drug development • Pharmacokinetic modeling: plasma concentration and tissue uptake • Study drug distribution: “peripheral” benzodiazepine receptor • Study drug metabolism: inhibit defluorination

  18. Brain Uptake of [18F]Fluoxetine: Measures Density of Serotonin Transporters & Affinity of Fluoxetine Patient Healthy Brain Drug AUC=32 AUC=16 Time Time

  19. Brain Uptake of [18F]Fluoxetine: Measures Density of Serotonin Transporters & Affinity of Fluoxetine Patient Healthy Brain Drug AUC=32 AUC=16 Time Time

  20. Brain Uptake of [18F]Fluoxetine: Measures Density of Serotonin Transporters & Affinity of Fluoxetine Patient Healthy Brain Drug AUC=32 AUC=16 Time Time

  21. Brain Uptake of [18F]Fluoxetine: Measures Density of Serotonin Transporters & Affinity of Fluoxetine Patient Healthy Brain Drug AUC=32 AUC=16 Time Time

  22. Brain Uptake of [18F]Fluoxetine: Measures Density of Serotonin Transporters & Affinity of Fluoxetine Patient Healthy Brain Drug AUC=32 AUC=16 Time Time

  23. Brain Uptake of [18F]Fluoxetine: Measures Density of Serotonin Transporters Patient Healthy Brain Drug AUC=32 AUC=16 Time Time

  24. Binding Potential (BP): Receptor Density * Affinity BP equals uptake in brain relative to how much drug is delivered via arterial plasma. Brain Drug AUC=16 Area Brain Curve BP = Area Plasma Curve 16 BP = = 8 2 Plasma Drug AUC=2 Time

  25. Binding Potential: Independent of Injected Dose* Double Plasma Input =>Double Brain Response 16 2 *If ligand does not saturate receptors - i.e., if tracer doses used AUC=32 Brain Drug BP 1st Time = = 8 32 AUC=16 BP 2nd Time = = 8 4 AUC=4 Plasma Drug AUC=2 Time

  26. K1 Plasma Brain k2 BP can be calculated from the Area Under Curve (math integral) as well as rate constants (math differential). From curves of plasma and brain radioactivity over time, estimate rate constants of entry and removal to/from tissue.

  27. Tissue uptake is proportional to density of receptors and the affinity of the drug Binding Potential

  28. SUMMARY PET KINETICS • Organ uptake is proportional to receptor density and affinity of drug • Binding Potential (BP) = density X affinity • “Drug Exposure” to tissue is AUC of: plasma concentration vs. time • “Response” (uptake) of tissue is AUC of: tissue concentration vs. time • BP also equals ratio of rate constants of entry and removal to/from tissue

  29. Major Point of PET Pharmacokinetics(in words) • Plasma pharmacokinetics provides a limited view of what’s happening to drug in plasma. • PET provides a limited view of what’s happening to drug in tissue. • Concurrent measurement of drug in plasma and of drug in tissue allows quantitation of the target of drug action – i.e., receptor.

  30. Pharmacokinetics: Drug in plasma Pharmacodynamics: Drug acts at receptor Receptor Density Receptor Density & Brain Drug & Plasma Drug Time Time

  31. Outline of Talk • PET has high sensitivity and specificity • PET used in therapeutic drug development • Pharmacokinetic modeling: plasma concentration and tissue uptake • Study drug distribution: “peripheral” benzodiazepine receptor • Study drug metabolism: inhibit defluorination

  32. Translocator Protein (18 kDa)a.k.a. “peripheral benzodiazepine receptor” • Mitochondrial protein highly expressed in macrophages and activated microglia • Exists in periphery and brain • Multiple potential functions: steroid synthesis, nucleotide transport • Distinct from typical benzodiazepine GABAA receptor in brain • Marker for cellular inflammation

  33. Receptor Blockade [11C]PBR28 in Monkey Brain: more radioligand in plasma and brain BASELINE RECEPTORS BLOCKED BP = 1.7 mL/cm3 BP = 130 mL/cm3 BRAIN PLASMA

  34. Receptor blockade displaces from lung & kidney. Drives more to brain but doesn’t bind there. Baseline Lungs Heart Spleen Kidneys Brain Blocked PK11195 10 mg/kg 2 min 115 min 25 min

  35. Incidental Stroke PET 6 weeks after MRI Original MRI (T1 ) Repeat MRI 8 weeks after PET Repeat MRI (FLAIR , edema)

  36. TSPO identifies epileptogenic focus in 15 of 16 patients. Hirvonen et al., JNM, 2012

  37. Human with low uptake is similar to monkey with receptor blockade A) regular healthy subject B) odd healthy subject D) pre-blocked monkey C) normal monkey

  38. No Binding to [11C]PBR28 in Brain and Periphery Lungs Heart Normal Binding Kidneys Spleen No Binding (~10% subjects) 2 min 26 min 103 min

  39. TSPO rs6971 polymorphism causes differential affinity for PBR28 • Ala to Thr substitution • Allelic frequency ~ 30%. • Prevalence of homozygotes ~ 9% • Codominant expression • HAB - high affinity binding • LAB - low affinity binding • MAB - reduced binding (mixed affinity states) Owen, JCBFM 2012

  40. Brain Uptake of [18F]Fluoxetine: Measures Density of Serotonin Transporters Patient Healthy Brain Drug AUC=32 AUC=16 Time Time

  41. Binding Potential (BP): Receptor Density * Affinity Brain Drug AUC=16 Area Brain Curve BP = Area Plasma Curve 16 BP = = 8 2 Plasma Drug AUC=2 Time

  42. Experimental Design: Effect of TSPO genotype on PBR28 binding • PET study • 27 healthy volunteers • In vitro binding: Leukocyte displacement assay • In vivo binding: [11C]PBR28 PET imaging • Post-mortem study • 47 healthy controls, 45 schizophrenia patients • Specific [3H]PBR28 binding in prefrontal cortex • Comparison with and without genotype correction Kreisl, JCBFM 2013

  43. PET Study: Both TSPO genotype and leukocyte binding assay determine affinity status HAB MAB % [3H] PK11195 specifically bound LAB Kreisl, JCBFM 2013 Owen, JCBFM 2012 100% agreement between binding assay results and genotype One-site fit = HAB Two-site fit = MAB

  44. PET Study: [11C]PBR28 binding is 1.4-fold higher in high affinity binders than mixed affinity binders Mean HAB = 4.5 mL • cm-3 Mean MAB = 3.2 mL • cm-3 Expect less than 2-fold difference because [11C]PBR28 uptake represents specific and nonspecific binding

  45. PET Study: Greater brain uptake in HH subjects with similar plasma concentration as HL subjects ○ HAB ● MAB

  46. Post-mortem study: High and mixed affinity binders also seen in schizophrenia patients Kreisl, JCBFM, 2013

  47. Correcting for TSPO genotype increases sensitivity to detect difference between schizophrenia and controls Without genotype as covariate p = 0.085 With genotype as covariate p = 0.011

  48. Summary • PBR28 PET study: • Leukocyte binding assay predicts TSPO genotype • TSPO genotype influences [11C]PBR28 total binding • PBR28 Post-mortem study: • TSPO genotype influences specific binding • Genotype correction increases ability to measure difference in schizophrenia and controls • Correcting for TSPO genotype expected to improve clinical use of [11C]PBR28

  49. Outline of Talk • PET has high sensitivity and specificity • PET used in therapeutic drug development • Pharmacokinetic modeling: plasma concentration and tissue uptake • Study drug distribution: “peripheral” benzodiazepine receptor • Study drug metabolism: inhibit defluorination

  50. [18F]FCWAY: Defluorination Bone uptake: human skull at 2 h

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