HER2-HER3 signaling can be inactivated by doses of lapatinib that fully inactivate the HER2 kinase. In mouse models, such doses are not tolerable in continuous administration, but they are tolerable and highly effective in intermittent dosing. We pursued the clinical translation of this treatment hypothesis. Patients and Methods We conducted a phase I dose-escalation study in women with advanced HER2-overexpressing breast cancer. Lapatinib was administered on days 1 through 5 of repeating 14-day cycles. Dose escalation was conducted using a 3+3 design with plasma lapatinib level monitoring. Results Forty patients were evaluable for toxicity, and 34 patients were evaluable

for dose-limiting toxicity (DLT). Lapatinib dose was escalated to 7,000 mg per day in learn more twice-daily dosing with no DLTs; however, plasma lapatinib concentrations plateaued in this dose range. Additional cohorts evaluated strategies to increase lapatinib exposure, including the food effect, CYP3A4 inhibition, and dose fractionation. Of these, only ketoconazole was able to increase lapatinib exposure, despite highly variable lapatinib bioavailability. Intolerable exposure levels were not encountered. Eight patients (20%) experienced grade 3 diarrhea. Six patients achieved DMXAA manufacturer a response, and dramatic responses were seen in three patients with lapatinib concentrations approaching 10,000

ng/mL. Conclusion Lapatinib exposure can be safely and significantly increased through intermittent dosing but reaches a ceiling that currently impedes clinical translation of the treatment hypothesis. SNX-5422 Preliminary efficacy data suggest that exposures approaching those seen in mouse models can result in highly significant tumor responses.”
“Variability in the rate of nicotine metabolism, measured by the nicotine metabolite ratio (NMR), is associated with smoking behavior. However, data linking the NMR with nicotine dependence measured by the Fagerstrom test for nicotine dependence

(FTND) are mixed. Few past studies have examined alternative measures of nicotine dependence and how this relationship may vary by sex and race. Using data from smokers undergoing eligibility evaluation for a smoking cessation clinical trial (n = 833), this study examined variability in the relationship between NMR and nicotine dependence across sex and race and using three measures of nicotine dependence: FTND, time-to-first-cigarette (TTFC), and the heaviness of smoking index (HSI). Controlling for sex and race, nicotine metabolism was associated with nicotine dependence only when using the HSI (p smaller than 0.05). Male normal metabolizers of nicotine were more likely to have high nicotine dependence based on the FTND and HSI (p smaller than 0.05), but NMR was not related to measures of nicotine dependence in women. For African Americans, the NMR was associated with nicotine dependence only for the TTFC (p smaller than 0.