Antitumor efficacy of AG3340 associated with maintenance of minimum effective plasma concentrations and not total daily dose, exposure or peak plasmaconcentrations

Oral administration of AG3340, a novel metalloprotease (MMP) inhibitor, sup presses the growth of human colon adenocarcinoma (COLO-320DM) tumors in viv o (Proc Am Assoc Cancer Res 39: 2059, 1998). In this report, we tested the hypothesis that the growth inhibition of these tumors is associated with ma intaining minimum effective plasma concentrations of AG3340. Nude mice were given a total oral daily dose of 25 or 200 mg/kg; 6.25 mg/kg was given fou r times per day (QID) (25 mg/kg/day), and 100 mg/kg was given in two daily doses (BID) (200 mg/kg/day). Peak plasma concentrations (C-max) of 83 +/- 4 3 (mean +/- SD) and 1998 +/- 642 ng/ml were detected 30 min after a single dose with 6.25 mg/kg and 100 mg/kg AG3340, respectively. AUC((0-24 h)) valu es estimated from dosing with 25 and 200 mg/kg/day AG3340 were 672 and 1088 2 ng*h/ml, respectively. Importantly, both regimen inhibited tumor growth e quivalently (74 to 82%). Efficacy was also compared at a total daily dose o f 25 mg/kg by giving AG3340: QID (6.25 mg/kg per dose), BID (12.5 mg/kg per dose), and once daily (25 mg/kg per dose). The C-max of these regimens was 83 +/- 43, 287 +/- 175 and 462 +/- 495 ng/ml, respectively. AG3340 did not inhibit tumor growth with the latter two regimens. The efficacy of 6.25 mg /kg QID (25 mg/kg/day) was superior to the efficacy of 25 mg/kg BID (50 mg/ kg/day), substantiating the independence of efficacy from the total daily d ose and C-max. Expectedly, peak to trough fluctuations were significantly s maller with the QID regimen than with BID and QD dosing. After 24 h, the tr ough was greater than 1 ng/ml with QID dosing but was less than 1 ng/ml aft er QD and BID dosing. These results suggest that the antitumor efficacy of AG3340 was associated with maintaining minimum effective plasma concentrati ons of AG3340 and demonstrate that the antitumor efficacy of AG3340 was ind ependent of the total daily dose, peak plasma concentration, and drug expos ure in this tumor model.