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Tutorials : Nov 1, 2008 ( )
Using Microdosing to Enhance Development
Early Availability of PK Information Allows for Selection of Potentially Promising Molecules
For a biotech company seeking to discover and develop novel drugs, microdosing offers an opportunity to reduce risk, cost, and the time required to confirm acceptable pharmacokinetics (PK) in man. Microdosing is a technique whereby experimental compounds are administered to humans in small doses (typically 1/100th of a therapeutic dose). The drug’s pharmacokinetics are then characterized through the use of sensitive detection techniques.
Described in its simplest terms, microdosing is the administration to a human subject of a subpharmacological and subradiological dose of a 14C-labeled drug candidate by either or both the IV and oral route. The primary product of these studies is human PK with absolute bioavailability.
The benefits of microdosing are particularly powerful for the anti-infective arena where PK is the key hurdle for clinical success. In companies where the discovery platform allows the parallel advancement of multiple, structurally distinct candidates, these benefits are compounded. The early availability of oral/IV human PK, distribution, and metabolism data, albeit at low doses, allows early selection of a candidate with the best probability of success in man while creating advanced back-ups should they be needed.
Antibiotic Drug Development
Historically, antibiotic drug development has benefited from the clearly established predictive relationship of microbiology, mouse infection models, and human efficacy. Therefore, confirming the translation of animal PK into man remains the most significant hurdle for successful new antibiotic drug development.
Microdosing, with its rapid turnaround and significantly reduced cost, offers the opportunity to evaluate multiple compounds in man and hence select the optimal development candidate based on both antimicrobial potency and the best human PK profile—markedly increasing the odds of ultimate clinical and commercial success.
In recent years, numerous new technologies have been brought to bear on enabling innovation, accelerating progress, and increasing the success rate in drug discovery. A motivation for this effort has been to rein in the dramatic growth in the cost to both discover and to bring new products to market faster and for less cost.
The exceptional advances made in developing and applying these discovery technologies have, for the most part, not been matched by changes within clinical development. It is against this backdrop that the advent of microdosing and exploratory or Phase 0 development has gained acceptance and support from both the EMEA and the FDA. It is now slowly building a dedicated following within the biotech and pharmaceutical industry.
As a result of its ultrasensitivity, the associated analytical methodology can also provide selected data on drug tissue distribution including skin and lung concentrations, as well as early data on primary human metabolism. This new clinical approach to risk reduction has been pioneered by Xceleron.
Because of the small doses or microdoses that are administered to human subjects, minimal rodent safety evaluation is required and as a consequence, the need to manufacture significant and expensive quantities of GLP and GMP API to support normal Phase I development is obviated. Comparing typical Phase I to Phase 0 expenditures, up to a 10-fold reduction in cost is often possible.
This level of cost reduction and timeline acceleration to generate human PK has enabled the direct and almost parallel comparison of several clinical candidates to be made. This approach reduces the risk of selecting a suboptimal candidate and/or failing in Phase I as a result of poor human PK.
Traditionally, antibiotic development has enjoyed a reduced rate of attrition as compared to other therapeutic areas. Antibiotics successfully completing Phase I evaluation are much more likely to make it to the NDA stage than a new compound to treat depression or hypertension.
The rationale for this observation is that since antibacterials treat infections caused by exogenous invading organisms rather than addressing a malfunction of an endogenous physiological function, efficacy is highly predicted by animal infection models. In many respects, this reduces the challenge of developing antibiotics to one of satisfying requirements for acceptable human pharmacokinetics and tolerability. This is the environment in which the Rib-X platform is positioned to exploit microdosing with new families of antibiotics derived from its technology platform that visualizes antibiotics bound to the 50S subunit of the bacterial ribosome.
Graham Johnson, Ph.D. (gjohnson@ rib-x.com), is chief research officer at Rib-X Pharmaceuticals. Web: www.rib-x.com.
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