Pharmacokinetics analysis of AT on SCID mice bear

Pharmacokinetics analysis of AT-406 on SCID mice bearing MDA-MB-231 tumors has shown that AT-406 achieves a maximum concentration in plasma between 1.5μM and 9.9μM, and a maximum concentration in tumor tissue between 0.5μM and 18.2μM, depending on the dose and administration route (intravenous versus oral gavage) [11]. Therefore, the described effects of AT-406 concentrations ranging from 100 nM to 1μM may be further increased in vivo. Results from this work indicate that despite the anti-tumoral effect of AT-406, its use in the context of bone metastatic disease needs to be carefully monitored for the induction of increased bone resorption. In this case, the use of AT-406 with an anti-resorptive agent could be beneficial. The combination of AT-406 with bisphosphonates for example could compensate for the increase in bone resorption. We also hypothesize that the combination of AT-406 with anti-RANKL directed therapies could have a beneficial effect, especially in RANK-positive tumors. In these cases, the lack of available RANKL could prevent the induction of metastatic phenotype of cancer Mifepristone triggered by RANK activation, decrease the de novo osteoclastogenesis, and increase the apoptosis of mature osteoclasts via AT-406.
Conflict of interest statement
Acknowledgments The authors want to acknowledge Ascenta for providing AT-406, and Dr. Mike Rogers for providing RAW264.7 cells. S. Casimiro and I. Alho are supported by fellowships from FCT (SFRH/BPD/34801/2007 and SFRH/BD/44716/2008, respectively).
Background Bone is the most common site of breast cancer recurrence [1]. Patients diagnosed with bone metastases are presently treated with bone-targeting agents, such as bisphosphonates and RANK ligand antibodies, every 3–4 weeks for the remainder of their life [2]. Historically, the frequency of dose administration was developed partly on schedules based on hypercalcaemia trials and limited bone marker studies but also for convenience rather than efficacy and safety purposes, as it allowed investigators to deliver bone-targeted agents at the same time patients were also receiving chemotherapy (i.e. every 3 weeks) or every 4 weeks if the patient was receiving endocrine therapies. However, this rationale ignores the pharmacokinetics of BTAs, which may have a half-life in bone of many years [3,4], and the modest absolute magnitude of benefit of these agents [5]. Despite the widespread use of BTAs, the question around optimal dose and dosing intervals remains unanswered [6–8]. This is particularly important given that drug induced toxicities are directly related to both the potency of the agent and also the cumulative dose received. Indeed, the incidence of BTA-associated osteonecrosis of the jaw is now approaching 10% in some selected chart reviews and online registries, making this by far the most common and serious side effect of treatment [9]. A number of reported pilot studies [10–13] have suggested that patients can derive similar palliative benefits from bone-targeted agents when given at less frequent intervals, while others are ongoing [14]. While we have previously used the term de-escalation to imply reduced frequency of administration [11] it can also relate to a reduced dose per unit time. In order to assess the need for further randomized controlled trials of standard 3–4 week treatment with bone-targeted agents in breast cancer patients with metastatic disease compared to de-escalated treatment, we performed a systematic review of the published literature.
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Introduction According to WHO classification, PBL is defined as a mono-ostotic disease with or without involvement of regional lymph nodes, or as a poly-ostotic disease affecting multiple skeletal sites without visceral- or lymph node involvement [1].