Defining the optimal biologic dose (OBD) of an AI will ultimately be of primary importance in AI drug development, but it will also be the most challenging aspect of the drug to define. The OBD of an AI may be very different than the MTD. If one relies entirely on the MTD to identify the appropriate dose of the AI for a phase II trial, patients may be subjected to a dose of drug associated with toxicity in excess of what might be expected using the OBD dose. More importantly, exceeding the OBD may negate the desired biologic effect (Fig. 1). The "more is better" credo may not necessarily apply to cytostatic agents, such as AIs.
The experience with cytostatic hormonal agents in the treatment of metastatic breast cancer is particularly instructive in this respect. Tamoxifen is the endocrine therapy of choice for all stages of breast cancer, and the most prescribed cancer medication in the world (20). The antitumor effect of tamoxifen is mediated primarily through the estrogen receptor (ER). The tamoxifen-ER complex that is formed is incompletely converted to the activated form (e.g., estrogen-ER complex), and as a result the complex is only partially active in initiating the programmed series of events necessary to initiate gene activation required for cell growth and proliferation (20). Early clinical trials of tamoxifen demonstrated that, although higher daily doses than the standard of 20 mg/d did not result in a significant increase in acute toxicity, there was no additional antitumor activity, defined as an increase in ORR (e.g., CR + PR + SD) (20). It is now appreciated that chronic administration of tamoxifen at does higher than 20 mg/d may be associated with an increase risk of endometrial carcinoma and thromboembolism (20).
Another example that demonstrates this concept is the use of the new aromatase inhibitor, anastrozole, for the treatment of metastatic breast cancer. Anastrozole, as opposed to its predecessor, aminoglutethimide, is a selective aromatase inhibitor that blocks the conversion of androstenedione to estrone. The drug is most effective in post-menopausal women with ER-positive tumors, in whom nonovarian sites of aromatase activity predominate (i.e., adipose tissue, liver, muscle) (21). During the development of anastrozole, several doses of drug were evaluated to determine the dose that most effectively suppresses estradiol levels (21). A daily dose of 1 mg anastrozole was optimal, and, even in the pivotal clinical trial, there was no advantage to higher daily doses of anastrozole in terms of ORR. These examples support the notion of seeking the OBD, rather than the MTD, to guide AI development.
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