Given the very small sample size included in most tolerability studies, under strict a priori criteria small numbers of AEs can drive the MTD determination. When AEs are of questionable relationship to the study drug or are reported by SYN-117 mw unreliable patients – or,

conversely, when safety issues are seen that do not easily fit the MTD criteria – rigid adherence mTOR inhibitor to an a priori definition could result in inappropriate dose selection for phase II trials. For this reason, the current phase Ib protocol included provisions for independent unblinded data review if needed to elucidate the tolerability profile, as well as flexibility to allow clinical judgment in the final determination of the MTD. Whether better patient tolerability can be attributed in this case to alteration of receptor activity by previous antidepressant treatment is an open question. Currently marketed antidepressants are thought to have eventual downstream effects on the glutamate Tanespimycin ic50 system[35] and on AMPA receptors themselves,[36] suggesting that a prior treatment history could influence tolerability

even with this novel compound. However, we note that in the current trial, patients presenting with their first episode of depression (with no prior antidepressant taken in that episode) and those presenting with recurrent depression (and presumably a more robust treatment history) demonstrated very comparable tolerability profiles. Alternative explanations include the possibility that alteration of receptor activity by depression itself drives better tolerability in patients. Indeed, there is a growing body of evidence

suggesting that both glutamate activity[22–24] and AMPA receptor expression[36] are altered in depressed patients. However, the mechanism by which these findings translate into decreased glutamate drug sensitivity remains to be explored. As a result of this detailed bridging work and further information from 3-mercaptopyruvate sulfurtransferase animal and human pharmacokinetic/pharmacodynamics modeling, which predicted target levels of AMPA receptor engagement at doses ranging from 100 to 400 mg bid,[37] the upper end of the dose range selected for phase II efficacy trials was significantly higher than the HV MTD. Final dose selection also took into consideration the likelihood that patient tolerability could differ in an outpatient setting, where life demands may mediate the functional impairment associated with drug-related AEs. Here too, patient tolerability data helped to address this question by providing critical information regarding the time of onset, severity, and duration of AEs, and the tendency for specific events to abate over time. The Org 26576 bridging data therefore contributed to confident dose selection for phase II trial planning and, as a result, served the greater purpose of patient and program risk minimization. Acknowledgments Drs.