A phase I study of SR-4554 via intravenous administration for noninvasive investigation of tumor hypoxia by magnetic resonance spectroscopy in patients with malignancy.
OBJECTIVE
To perform a Phase I study of SR-4554, a fluorinated 2-nitroimidazole noninvasive probe of tumor hypoxia detected by (19)F magnetic resonance spectroscopy (MRS).


METHODS
SR-4554 administration, on days 1 and 8, was followed by plasma sampling for pharmacokinetic studies and by three MRS studies performed over 24 h on days 8 and 9. Unlocalized MR spectra were acquired from tumor (10- or 16-cm dual resonant 1H/19F surface coil; 1.5 T Siemens Vision MR system; 2048 transients acquired over 34 min; 1.28-ms adiabatic pulse; repetition time, 1 s). Plasma drug concentrations were measured with a validated high-performance liquid chromatography method. Noncompartmental pharmacokinetic analysis was performed.


RESULTS
Eight patients underwent pharmacokinetic studies, receiving doses of SR-4554 of 400-1600 mg/m(2). Peak plasma concentrations increased linearly with the SR-4554 dose (r(2) = 0.80; P = 0.0002). The plasma elimination half-life was relatively short (mean +/- SD, 3.28 +/- 0.59 h), and plasma clearance was quite rapid (mean +/- SD, 12.8 +/- 3.3 liters/h). Urinary recovery was generally high. SR-4554 was well tolerated. A single patient experienced dose-limiting toxicity (nausea and vomiting) at 1600 mg/m(2). The maximum tolerated dose was 1400 mg/m(2). SR-4554 was detected spectroscopically in tumors immediately after infusion at doses of 400-1600 mg/m(2). At the highest dose (1600 mg/m(2)), SR-4554 was detectable in tumor at 8 h, but not at 27 h.


CONCLUSIONS
SR-4554 has plasma pharmacokinetic and toxicity profiles suitable for use as a hypoxia probe. It can be detected in tumors by unlocalized MRS. Additional clinical studies are warranted.
Seddon
Beatrice M
BM
Cancer Research UK Centre for Cancer Therapeutics, Institute of Cancer Research, Sutton, Surrey, United Kingdom.
Payne
Geoffrey S
GS
Simmons
Laura
L
Ruddle
Ruth
R
Grimshaw
Rachel
R
Tan
Siew
S
Turner
Alison
A
Raynaud
Florence
F
Halbert
Gavin
G
Leach
Martin O
MO
Judson
Ian
I
Workman
Paul
P
D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000009:adverse effects / Q000493:pharmacokinetics*; D002851:Chromatography, High Pressure Liquid; D005260:Female; D005462:Fluorine Radioisotopes; D006207:Half-Life; D006801:Humans; D000860:Hypoxia / Q000175:diagnosis / Q000378:metabolism*; D007262:Infusions, Intravenous; D009682:Magnetic Resonance Spectroscopy / Q000379:methods*; D008297:Male; D020714:Maximum Tolerated Dose; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D009369:Neoplasms / Q000175:diagnosis / Q000378:metabolism*; D009593:Nitroimidazoles / Q000009:adverse effects / Q000493:pharmacokinetics*
D014408:Biomarkers, Tumor; D005462:Fluorine Radioisotopes; D009593:Nitroimidazoles; C095171:SR 4554