M. Simpson1, G. Lappin2, C. Wagner3, O.Langer3, I. Morris4

1University of York, York, UK2Xceleron Inc, Gaithersburg, MD, USA

3Medical University of Vienna, Vienna, Austria 4Hull York Medical School, York, UK

Overview

Accelerator Mass SpectrometryPositron Emission TomographyCombining AMS/PETClinical DesignAMS/PET Data SummaryConclusions/Applications

Accelerator Mass Spectrometry Isotope ratio techniqueOriginally developed for radiocarbon datingExtremely sensitiveTypically used with 12C/14C

Accelerator Mass Spectrometry

Ion source

Injection magnet

Linearaccelerator

Analysingmagnet

12C13C

14C

High energyallows separationof rare 14C fromother isotopes99.8%

1.1%

10-11%

Positron Emission TomographyPET

Non-invasive nuclear imaging techniqueTissue distribution Drug labelled with positron emitting radionuclide (e.g. 11C or 18F)

Positron Emission Tomography

PET Camera

11C 11B + β+ + v + energy (97keV)

β+

11C

PET Camera

AMS & PETAMS

Prolonged PK dataLimitation – no distribution information

PETPK in tissueLimitation – short term PK only

CombinationLong term PK (AMS)Brain PK (PET)

IN THE SAME SUBJECTS

Clinical DesignAdministration of verapamil

Calcium channel inhibitorP-glycoprotein substrate, crosses blood-brain-barrierWell documented safety and PK profileIV dual labelled (R/S)-[14C], (R)-[11C] verapamil (50 µg)

Chiral centrePosition of dual label (11C and 14C)

Clinical Design (2)

IV Verapamil = 50 µg(R/S)-[14C] (4.1kBq), (R)-[11C] (407 MBq)PET scan/arterial plasma collection (0-60 minutes)Venous plasma collection (0-24 hours)MRI scan

Period 1 Period 2IV dual-labelled

verapamil (50 μg)

7 healthy male volunteers

IV dual-labelled

verapamil (50 μg)

7 healthy male volunteers

Oral verapamil (80 mg)

Aims

To establish a protocol for microdosing studiesR-verapamil in brain by PET R- and S-verapamil in plasma by AMS

Assess PK linearity between therapeutic dose and microdose

Quantification of R- and S-verapamil by HPLC-AMS

Separation of R- & S-verapamil by 2D C18-chiral HPLC

R-verapamilS-verapamil

Plasma Data Summary

R-verapamil

Microdose Microdose + therapeutic dose

Plasma PK Data SummaryParameter Enantiomer Microdose

Microdose + therapeutic

dose

t1/2 (h)R 6.3 ±1.9 6.9 ±1.6

S 7.2 ±2.5 7.1 ±2.2

Cmax (pg/mL)R 210.1 ±79.2 243.8 ±77.7

S 96.3 ±28.6 103.5 ±33.6

AUC(0-24) (hpg/mL)R 579.8 ±107.4 794.0 ±265.1

S 272.6 ±70.7 313.8 ±59.7

AUC(0-inf) (hpg/mL)R 624.5 ±131.6 843.2 ±281.1

S 308.6 ±79.3 343.3 ±58.9

CL (L/h)R 61.0 ±12.6 46.9 ±10.9

S 89.7 ±24.2 78.2 ±14.7

V (L)R 528.2 ±95.1 465.7 ±133.0

S 912.9 ±341.9 789.0 ±272.8

Vss (L)R 397.9 ±89.8 319.9 ±68.7

S 682.0 ±167.0 600.6 ±187.6

PET Data Summary

SUVPET therapeutic dosePET micro dose MRI

2.8

0

PET Data Summary

Arterial plasma Whole brain grey matter

Total 11C

11C-R-verapamil

PET Data SummaryParameter Microdose

Microdose +therapeutic

dose

K1 (mLmL-1min-1) 0.030±0.003 (10) 0.031±0.005 (8)

k2 (min-1) 0.099±0.006 (49) 0.095±0.008 (40)

k3 (min-1)

k4 (min-1)

0.100±0.001 (90)

0.092±0.029 (26)

0.101±0.000 (96)

0.159±0.063 (42)

DV (mLmL-1) 0.66±0.12 (4) 0.56±0.11 (2)

DV (Logan) (mLmL-1) 0.66±0.11 (2) 0.57±0.11 (1)

ConclusionsPrinciple of AMS/PET combination demonstratedLong term plasma PK obtained along with tissue

distribution informationVerapamil shown to be dose linear

Plasma (by AMS)Brain (by PET)

S-verapamil shows preferential clearanceProof of concept for combination studies

Applications in brain, tumour, cardiac therapy

Acknowledgements

PET team - Medical University of Vienna

University of York

Xceleron Ltd