Clinical pharmacokinetic and pharmacodynamic studies with the nonclassical antifolate thymidylate synthase inhibitor 3, 4-dihydro-2-amino-6-methyl-4-oxo-5-(4-pyridylthio)-quinazolone dihydrochloride (AG337) given by 24-hour continuous intravenous infusion.
3,4-Dihydro-2-amino-6-methyl-4-oxo-5-(4-pyridylthio)-quinazolon e dihydrochloride (AG337) is a nonclassical inhibitor of thymidylate synthase (TS) designed to avoid potential resistance mechanisms that can limit the activity of classical antifolate antimetabolites. A clinical pharmacokinetic and pharmacodynamic study of AG337 given as a 24-h i.v. infusion was performed. Thirteen patients received 27 courses over the dose range 75-1350 mg/m2. Plasma AG337 concentrations were achieved which, in preclinical models, were associated with antitumor effects. AG337 clearance was saturable, and the pharmacokinetics of the drug at doses above 300 mg/m2 was best described by a one-compartment model with saturable elimination (median Km = 6.5 microgram/ml; range, 4.1-13 microgram/ml; median Vmax = 2.0 microgram/ml/h/m2; range, 0.96-5.6 microgram/ml/h/m2). Following the end of the infusion, AG337 was cleared rapidly (t1/2, 53-193 min), and levels were less than 0.2 microgram/ml in all patients by 48 h. Plasma protein binding was 96-98%, and the urinary excretion of AG337 as unchanged drug did not exceed 30% of the dose administered. Measurements of plasma deoxyuridine (dUrd) concentrations showed that doses of 600 mg/m2 and above of AG337 produced a consistent elevation in plasma dUrd levels (60-290%), suggesting that TS inhibition was being achieved in patients. However, in all cases dUrd concentrations had returned to pretreatment levels 24 h after the end of the infusion, suggesting that TS inhibition was not maintained. Local toxicity, probably due to the infusate pH, was the only significant adverse effect observed. These studies have shown that cytotoxic AG337 plasma concentrations can be readily achieved without acute toxicity and that these concentrations are associated with elevations in plasma dUrd levels. The lack of prolonged dUrd elevations indicates that extended administration should be explored using central line or p.o. administration to avoid local toxicity.
Rafi
I
I
Cancer Research Unit, Medical School, University of Newcastle upon Tyne, Framlington Place, Newcastle, NE2 4HH, Newcastle General Hospital, Newcastle, NE4 6BE, United Kingdom.
Taylor
G A
GA
Calvete
J A
JA
Boddy
A V
AV
Balmanno
K
K
Bailey
N
N
Lind
M
M
Calvert
A H
AH
Webber
S
S
Jackson
R C
RC
D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D004334:Drug Administration Schedule; D003875:Drug Eruptions / Q000188:drug therapy / Q000209:etiology; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D005260:Female; D005493:Folic Acid Antagonists / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D011799:Quinazolines / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors*
D000964:Antimetabolites, Antineoplastic; D004791:Enzyme Inhibitors; D005493:Folic Acid Antagonists; D011799:Quinazolines; D013940:Thymidylate Synthase; C099178:nolatrexed