| The goal of this research was to determine the safety, tolerability and pharmacokinetics (PK) and pharmacodynamics (PD) of COL-3 in patients with refractory metastatic cancer, as assessed by matrix metalloproteinase inhibition in plasma and clinical toxicity. The primary objective of this research was to test the following hypotheses: (1) Since COL-3 is a more lipophilic tetracycline derivative, the terminal half-life will be prolonged and the volume of distribution will be larger than tetracycline and doxycycline. (2) COL-3 will exhibit linear PK. Single-dose PK parameters will be useful in predicting steady-state concentrations. (3) The plasma protein binding will be linear in the ‘clinically achievable’ concentration range.(4) The photosensitivity observed with COL-3 is not dose-dependent. (5) Since the inhibition of matrix metalloproteinase (MMP) production occurred at concentrations of 1000 to 10000 ng/ml in vitro, the same effect will be observed in vivo at similar concentrations.; Results from this study demonstrate that: (1) COL-3 had a longer half-life (median = 56.7 hr, range = 23.7–144.4 hr, n = 34) and a larger volume of distribution (median = 801.8 L, range = 458.5–2074.8 L, n = 34) than tetracycline (9.9 hr, 108.7 L) and doxycycline (26.1 hr, 62.7L); (2) There was non-linear pharmacokinetics as demonstrated by a less than dose-proportional increase in Cmax and AUC0–∞ after single dose administration, probably due to the low GI solubility of COL-3. Furthermore, single-dose PK did not predict multiple-dose PK in most patients, possibly due to changes in metabolism (3) there was nonsaturable PPB of COL-3 (fu = 5.5%) in the clinically achievable concentration range between 30 and 30000 ng/ml; (4) there was dose-dependency associated with the photosensitivity; (5) there was a decrease in MMP-2 levels (pro-MMP and pro-MMP complexed with TIMP) but not MMP-9 in plasma in vivo in some but not all patients. In addition, COL-3 undergoes glucuronidation in vitro by UGT1A1, UGT1A3, UGT1A9, and UGT2B7, and in vivo as evidenced by COL-3 glucuronides in the urine (median = 13.6% of the total dose; range = 4.0–24.0%). (Abstract shortened by UMI.)... |
