Innovation Pharmaceuticals Inc (IPIX)

[farrell90]

Brilacidin has important qualities which allows once daily dosing. First of all it is quickly bactericidal.

Although we do not know the results of the PK-PD studies for Brilacidin it is reasonable to infer its half life and protein binding allow satisfactory volume distribution to achieve adequate tissue levels.

Kevetrin is more difficult. With many cancer agents dosing is dictated by their toxicity and biologic effect. Since Kevetrin seems to be relatively non toxic, even at higher doses. It may allow more frequent dosing; maybe even daily.

Many of the new biologic agents such as monoclonal antibodies for cancer fit into the same category; relatively low toxicity with targeted biologic activity.
The concept of optimal biologic effect describes the pharmacologic goal for these drugs.

"For these agents, the “optimal biologic dose” might be that which results in saturation of a target or which produces the desired biologi-cal e?ect, such as blockade of the targeted signaling pathway. Pharmacodynamic end points that assess target inhibition may be more relevant for these agents".

http://onlinelibrary.wiley.com/doi/10.1038/clpt.2014.153/abstract;jsessionid=B793E870D365944A5580F5448818342C.f03t04

THE NEED FOR IMPROVED DOSING IN ONCOLOGY
Balancing the bene?ts and risks of cancer therapies is critical in order to provide longer survival while maintaining or improv-ing patients’ quality of life. A key to achieving this balance is identifying the dose at which e?cacy is maximized and toxicity is minimized; a dose that is too high can render an otherwise-e?ective drug intolerable, whereas a dose that is too low can result in failure to achieve the expected therapeutic bene?t of a drug. Despite the best e?orts of drug developers, dose opti-mization is challenging; in fact, inability to ?nd the best dose for registration trials is a common factor in the denial of new drug applications across all therapeutic areas by the US Food and Drug Administration (FDA).1 ?is challenge is heightened in the case of cancer due to its life-threatening nature: A high degree of drug toxicity is generally considered acceptable for a drug that is e?ective, and the need to develop e?ective new drugs quickly o?en takes precedence over the need to ?nd the “right” dose, which, even when de?ned, is only an estimate for a certain patient population. For any drug dose, a range of ben-e?cial and toxic e?ects can be anticipated that will vary based on the unique characteristics of each patient receiving the agent. An evaluation of recently approved oncology drugs demonstrates that some of these agents are labeled for use at doses that may be either too high or too low (Table 1), indicating that our cur-rent approach to dose selection needs improvement. For patients to fully bene?t from the great strides being made in develop-ing new treatments for cancer, it is important that we devise a comprehensive drug-development strategy that includes dose optimization but does not unnecessarily delay market entry for potentially important new drugs.In the current oncology drug development paradigm, trials are designed to maximize the chance of obtaining an e?cacy sig-nal and are o?en performed in heavily pretreated patients with advanced disease and limited life expectancy. ?e objective of phase I trials is to determine the highest tolerable dose, based on the assumption that higher doses will provide greater e?cacy. In these trials, increasing doses of a drug are sequentially evaluated generally during the ?rst two treatment cycles in small cohorts of patients until a prespeci?ed rate of dose-limiting toxicity is reached.2 ?e dose immediately below that which elicited dose-limiting toxicity is considered the maximum-tolerated dose and, in most cases, is then used for phase II and subsequent phase III trials, which are used to evaluate drug activity and e?cacy, respectively. It is rare for phase II or III studies of oncology drugs to evaluate more than one dose, although this approach is com-mon in other therapeutic areas. ?is traditional paradigm has several limitations. One is that it does not adequately evaluate interpatient variability in treatment response and toxicity: some patients may require a higher dose to achieve clinical bene?t, whereas other patients may ?nd the recommended phase II dose to be intolerable. In other terms, dose– or exposure–response relationships are rarely well de?ned for oncology drugs despite their o?en-narrow therapeutic index. ?e lack of such informa-tion o?en leads to a high rate of dose reductions in cancer clini-cal trials as well as failure to identify patients who may bene?t from a higher dose. ?is approach was designed to maximize the dosing of cytotoxic chemotherapy; however, many agents, such as those used in hormonal or targeted therapies, may achieve maximum e?cacy at a dose below the maximum-tolerated dose, or the maximum-tolerated dose may never be de?ned. For these agents, the “optimal biologic dose” might be that which results in saturation of a target or which produces the desired biologi-cal e?ect, such as blockade of the targeted signaling pathway.3 Pharmacodynamic end points that assess target inhibition may be more relevant for these agents, assuming that the drug target Received 29 May 2014; accepted 16 July 2014; advance online publication 17 September 2014. doi:10.1038/clpt.2014.153The purpose of this article is to acknowledge the challenges in optimizing the dosing of oncology drugs and to propose potential approaches to address these challenges in order to optimize effectiveness, minimize toxicity, and promote adherence in patients. These approaches could provide better opportunities to understand the sources of variability in drug exposure and clinical outcomes during the development and premarketing evaluation of investigational new drugs.1Division of Cancer Prevention, National Cancer Institute, Bethesda, Maryland, USA; 2Millennium: The Takeda Oncology Company, Cambridge, Massachusetts, USA; 3Multiple Myeloma Research Foundation, Norwalk, Connecticut, USA; 4Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland, USA; 5American Society of Clinical Oncology, Alexandria, Virginia, USA. Correspondence: RL Schilsky ([e-mail])Optimizing Dosing of Oncology DrugsL?Minasian1, O?Rosen2,