Pharmacokinetic assessment of novel anti-cancer drugs using spectral analysis and positron emission tomography: a feasibility study.
OBJECTIVE
The aim of this study was to investigate the feasibility of evaluating the pharmacokinetics of radiolabeled anti-cancer drugs using spectral analysis, a non-compartmental tracer kinetic modeling technique, and positron emission tomography (PET).


METHODS
Dynamic PET studies were performed on patients receiving tracer doses of 5-fluorouracil (5-[18F]-FU) and two developmental drugs [11C]-temozolomide and [11C]-acridine carboxamide. Spectral analysis was then used to (a) determine individual and group average pharmacokinetics, (b) predict tumour handling in response to different drug administration regimens, and (c) produce functional parametric images describing regional pharmacokinetics.


RESULTS
Spectral analysis could distinguish tumour kinetics from normal tissue kinetics in an individual [11C]-temozolomide study and demonstrated a markedly greater volume of distribution (VD) in glioma than in normal brain, although there was no appreciable difference in mean residence time. Analysis of pooled acridine carboxamide data (n = 22) revealed a relatively large VD (and prolonged retention) in the liver and spleen and a markedly lower VD (and initial uptake) in the brain. Continuous infusion of 5-[18F]-FU was predicted to achieve a concentration in colorectal metastases in liver approximately 10 times that achieved in plasma at 10 h after commencement of the infusion.


CONCLUSIONS
We conclude that spectral analysis provides important pharmacokinetic information about radiolabeled anti-cancer drugs with relatively few model assumptions.
PET and Nuclear Medicine Department, Royal Prince Alfred Hospital, Camperdown, NSW, Australia. steve@nucmed.rpa.cs.nsw.gov.au
S R
SR
Meikle
J C
JC
Matthews
C S
CS
Brock
P
P
Wells
R J
RJ
Harte
V J
VJ
Cunningham
T
T
Jones
P
P
Price
D000166:Acridines / Q000493:pharmacokinetics; D000964:Antimetabolites, Antineoplastic / Q000097:blood / Q000493:pharmacokinetics*; D018906:Antineoplastic Agents, Alkylating / Q000097:blood / Q000493:pharmacokinetics*; D015179:Colorectal Neoplasms / Q000378:metabolism; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D005240:Feasibility Studies; D005260:Female; D005472:Fluorouracil / Q000097:blood / Q000493:pharmacokinetics*; D005910:Glioma / Q000378:metabolism; D006801:Humans; D008875:Middle Aged; D013057:Spectrum Analysis / Q000379:methods; D000077204:Temozolomide; D014055:Tomography, Emission-Computed / Q000379:methods
D000166:Acridines; D000964:Antimetabolites, Antineoplastic; D018906:Antineoplastic Agents, Alkylating; D003606:Dacarbazine; D005472:Fluorouracil; D000077204:Temozolomide