Toremifene concentration and multidrug resistance in lung tumors

In this pharmacokinetics study, concentrations of toremifene (TOR), a new antiestrogen, were measured after a 7-day oral treatment in serum, lung, and tumor tissue to determine the optimal dose of TOR for the modulation of clinical multidrug resistance in patients with lung cancer. Target levels of the antiestrogen were based on previous in vitro studies. Altogether, 18 patients with operable lung tumors were studied. TOR was given in an open, nonrandomized, phase I study at three different dose levels. The medication consisted of oral TOR given for 7 days at either 240, 480, or 600 mg/day before surgical removal of the tumor. At least five patients were scheduled to be included at each dose level, with all five receiving the full course of therapy before escalation of the dose. Blood samples for serum TOR concentration measurements were taken on days 0 and 7. Specimens of tumor and normal lung tissue of approximately 0.5 g were taken on day 7. The concentrations of TOR and its metabolites were determined in serum, lung, and tumor tissue at different dose levels. Altogether, 12 evaluable patients completed the scheduled treatment. The concentrations measured in serum, lung, and tumor tissue increased along with the dose used, such that the highest TOR values were achieved at 600 mg/day, with mean values being 4.9 μmol/l, 175.0 μmol/g, and 122.7 μmol/g, respectively. The concentrations of TOR and its metabolite N-demethyltoremifene were highest in lung tissue, but the values measured in tumor specimens were also well above the respective concentrations detected in serum samples. The TOR doses of 240 and 480 mg/day were well tolerated. One patient in the group treated at 600 mg/day had to discontinue the treatment because of headache and nausea. TOR given at doses ranging from 480 to 600 mg/day for 7 days will produce serum, lung, and tumor concentrations of the parent drug and its metabolites that have been shown to reverse multidrug resistance of cancer cells in vitro. As the 480-mg/day dose of TOR produced tumor concentrations high enough to reverse multidrug resistance without producing adverse drug reactions, the dose recommended for the foreseen clinical trials in the reversal of multidrug resistance would be 480 mg/day for 7 days.