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Optivia builds on UCSF work to predict liver toxicity of drugs in development
MENLO PARK, Calif.—In a collaboration that could represent an important step forward toward ensuring drug safety and increasing drug efficacy by building the first transporter-based assay system capable of predicting ADME (absorption, distribution, metabolism and excretion) and reducing drug-induced liver toxicity, Optivia Biotechnology Inc. provider of in-vitro transporter assay services, will collaborate with the University of California, San Francisco (UCSF) to develop an innovative system for characterizing the role transporter proteins play in the disposition of drugs by the liver.
The partners have received a $430,000 Phase I grant to leverage the expertise of Dr. Leslie Z. Benet, an internationally recognized drug development expert and professor and chairman emeritus in UCSF's department of bioengineering and therapeutic sciences, along with Optivia's novel transporter technology platform to study the effects of transporters on drug disposition and the interplay of transporters and metabolizing enzymes in the liver.
The goal is to develop a transporter-based assay system capable of predicting the ADME characteristics of drug candidates. To do so, Optivia will screen 40 compounds against 10 transporters and work with UCSF to build a model based on the results.
Dr. Yong Huang, Optivia's president and CEO, says no specific indications will be studied, but notes that the liver is the major loci for metabolism of most drugs.
The Phase I study will also address the interplay between transporters and drug metabolizing enzymes.
The team will use the Biopharmaceutics Classification System (BCS), a guidance for predicting the intestinal drug absorption, to select 10 drugs from each of the four BCS categories. The Phase I program is a one year project. Phase II, Huang says, will extend to other organs—kidney, GI tract and blood-brain barrier—and extend the scope to study additional drugs.
"This collaboration reflects our response to the specific call from the pharmaceutical industry and regulatory agencies for systematic data, both in vitro and in vivo, with respect to how drugs interact with multiple transporters expressed in various human organs, and how such interactions alter drug pharmacokinetics in the human body," Huang states. "Integrating analysis of drug transporters is increasingly becoming a core requirement in ADME assessments and is anticipated to become a regulatory standard for new drug applications."
ADME models are increasingly influential in determining whether a new molecular entity should advance through R&D, and one of the fastest growing ADME research areas of the last decade is transporter proteins. It is estimated that more than 86 percent of all compounds and about 40 percent of clinical stage drugs fail due to unsatisfactory ADME, toxicity and clinical safety properties.
Drug-induced hepatotoxicity is estimated to be responsible for as many as 5 percent of all hospital admissions and 50 percent of all acute liver failures. Drug-induced liver toxicity is also one of the most common reasons for previously approved drugs to be withdrawn from the market, translating into increasing costs of drug discovery and development.
For example, according to the U.S. Food and Drug Administration's 2004 Critical Path Initiative white paper, it is estimated that clinical failures based on liver toxicity have cost one major pharmaceutical company more than $2 billion in the last decade.
"This grant will allow us to build on UCSF's previous work suggesting that we can predict how drugs will behave in the body, specifically the liver, based on transporter biology," says Benet, who is a member of the International Transporter Consortium.
"We intend to provide a body of systematic data based on the in-vitro profiling of a large number of drugs against a panel of key human transporters as the first step toward building transporter-based predictive models for the assessment of ADME and drug-drug interactions (DDIs). A model that correlates in-vitro data to in-vivo results would be of incalculable value to the pharmaceutical industry, since it will allow drug developers to make better decisions on the ADME properties of drug candidates prior to performing in-vivo studies, most likely reducing development costs and decreasing the number of failures related to the ADME properties of drugs," Benet adds.
Another next step, Huang says, may well be an FDA collaboration to determine how nutraceuticals interact in the liver with prescription and over-the-counter drugs to provide data that could be important to proposing regulations.