PI-51Population pharmacokinetics of COL-3, a matrix metalloproteinase inhibitor, in patients with refractory metastatic cancer

Abstract

PURPOSE COL‐3, a matrix metalloproteinase inhibitor, has been evaluated in phase I/II clinical trials for the treatment of cancer. The objective was to establish a population pharmacokinetic (PK) model of COL‐3 in cancer patients. METHODS 740 COL‐3 plasma concentration data were obtained from 34 cancer patients in a single‐dose, dose‐escalation (from 36 to 98 mg/m2/day) phase I study. Intense PK sampling was obtained after the first dose and trough concentrations were obtained throughout the treatment. A population PK model of COL‐3 was developed with first‐order conditional estimation using NONMEM. RESULTS A one‐compartment model with sequential zero‐order input, mimicking dissolution, and first‐order absorption and elimination described plasma concentration‐time profiles well. Estimated population means (RSE%) for apparent clearance and mean absorption time were 0.78 (6%) L/h and 1.8 (7%) h, with interindividual variability of 57% (40%) and 41% (27%), respectively. Covariate screening indicated that V/F was dose‐dependent, while body weight, body surface area, sex, age, and creatinine clearance did not exhibit any significant impact on COL‐3 PK. CONCLUSIONS A linear one‐compartment model with sequential zero‐ and first‐order absorption adequately describes COL‐3 PK in cancer patients. This population PK model supports fixed‐dosing of COL‐3. The dose‐dependence of Vd/F is likely the result of reduction in bioavailability (F) with increasing dose due to poor dissolution. Clinical Pharmacology & Therapeutics (2005) 79, P20–P20; doi:

Structure and properties of the new complexes of platinum (II) with the chemically modified tetracycline CMT-3: A theoretical DFT study

“…There are several works in literature discussing the efficacy of the CMT-3 [5][6][7][8][9][10][11][12][13], demonstrating that CMT-3 has both anti-tumor and anti-metastasis activity; its mechanism of action includes the inhibition of MMPs, induction of apoptosis and inhibition of cell proliferation [3,14]. Some advantages of CMT-3: it is an orally administrable anticancer drug, an MMP inhibitor combined with cytotoxic properties, little systemic toxicity and shows higher plasma accumulation leading to lower drug dose requirement [14].…”