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

This talk outlines the use of positron emission tomography (PET) as a tool to study pharmacokinetics and facilitate drug development. PET can measure receptor density, drug distribution, and drug metabolism, making it valuable in determining drug dose and dosing intervals, identifying homogeneous groups, and monitoring gene or stem cell therapies. Examples include imaging of dopamine transporter in Parkinson's disease and amyloid imaging for Alzheimer's disease.

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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 • Monitor gene or stem cell therapy

  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 • Monitor gene or stem cell therapy

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

  15. PET: Tool in TherapeuticDrug Development • Determine dose and dosing interval • Identify homogeneous group • Biomarker for drug efficacy • Monitor gene or stem cell therapy

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

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

  18. PET: Tool in TherapeuticDrug Development • Determine dose and dosing interval • Identify homogeneous group • Biomarker for drug efficacy • Monitor gene or stem cell therapy

  19. Gene Therapy Using Viral Vectors Viral vectors deliver gene that synthesizes dopamine (DA) Infuse virus into striatum (target cells) Target cells express the DA gene

  20. post pre pre post PET Dopamine Imaging in Hemi-Parkinson Monkey: Monitors gene for DA synthesis in right striatum Control Gene: Lac-Z DA Synthesis Gene: AADC

  21. 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

  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 & Affinity of Fluoxetine Patient Healthy Brain Drug AUC=32 AUC=16 Time Time

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

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

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

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

  28. 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

  29. 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

  30. 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.

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

  32. 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

  33. 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.

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

  35. 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

  36. 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

  37. 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

  38. 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

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

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

  41. 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

  42. 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

  43. 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

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

  45. 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

  46. 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

  47. [18F]FCWAY: Defluorination Bone uptake: human skull at 2 h

  48. [18F]FCWAY: Defluorination18F-fluoride ion accumulates in bone

  49. Temp Ctx Skull [18F]FCWAY: Miconazole Baseline 15 mg/kg 30 mg/kg 60 mg/kg Miconazole Inhibits Defluorination & Bone Uptake [18F]Fluoride Skull Brain

  50. Disulfiram: Decreases Skull Activity &Increases Brain Uptake Baseline Disulfiram Images at 2 h in same subject. Disulfiram 500 mg PO prior night

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