MENLO PARK, Calif.—In a collaboration that could representan important step forward toward ensuring drug safety and increasing drugefficacy by building the first transporter-based assay system capable ofpredicting ADME (absorption, distribution, metabolism and excretion) andreducing drug-induced liver toxicity, Optivia Biotechnology Inc. provider of in-vitro transporter assay services, will collaborate withthe University of California, San Francisco (UCSF) to develop an innovativesystem for characterizing the role transporter proteins play in the dispositionof drugs by the liver.
The partners have received a $430,000 Phase I grant toleverage the expertise of Dr. Leslie Z. Benet, an internationally recognizeddrug development expert and professor and chairman emeritus in UCSF'sdepartment of bioengineering and therapeutic sciences, along with Optivia'snovel transporter technology platform to study the effects of transporters ondrug disposition and the interplay of transporters and metabolizing enzymes inthe liver.
The goal is to develop a transporter-based assay systemcapable of predicting the ADME characteristics of drug candidates. To do so,Optivia will screen 40 compounds against 10 transporters and work with UCSF tobuild a model based on the results.
Dr. Yong Huang, Optivia's president and CEO, says nospecific indications will be studied, but notes that the liver is the majorloci for metabolism of most drugs.
The Phase I study will also address the interplay betweentransporters and drug metabolizing enzymes.
The team will use the Biopharmaceutics ClassificationSystem (BCS), aguidance for predicting the intestinal drug absorption, to select 10 drugs fromeach 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 andblood-brain barrier—and extend the scope to study additional drugs.
"This collaboration reflects our response to the specificcall from the pharmaceutical industry and regulatory agencies for systematicdata, both in vitro and invivo, with respect to how drugs interactwith multiple transporters expressed in various human organs, and how suchinteractions alter drug pharmacokinetics in the human body," Huang states."Integrating analysis of drug transporters is increasingly becoming a corerequirement in ADME assessments and is anticipated to become a regulatorystandard for new drug applications."
ADME models are increasingly influential in determining whethera new molecular entity should advance through R&D, and one of the fastestgrowing ADME research areas of the last decade is transporter proteins. It isestimated that more than 86 percent of all compounds and about 40 percent ofclinical stage drugs fail due to unsatisfactory ADME, toxicity and clinicalsafety properties.
Drug-induced hepatotoxicity is estimated to be responsiblefor as many as 5 percent of all hospital admissions and 50 percent of all acuteliver failures. Drug-induced liver toxicity is also one of the most commonreasons for previously approved drugs to be withdrawn from the market,translating into increasing costs of drug discovery and development.
Forexample, according to the U.S. Food and Drug Administration's2004 Critical PathInitiative white paper, it is estimated that clinical failures based on livertoxicity have cost one major pharmaceutical company more than $2 billion in thelast decade.
"This grant will allow us to build on UCSF's previous worksuggesting that we can predict how drugs will behave in the body, specificallythe liver, based on transporter biology," says Benet, who is a member of theInternational Transporter Consortium.
"We intend to provide a body ofsystematic data based on the in-vitroprofiling of a large number of drugs against a panel of key human transportersas the first step toward building transporter-based predictive models for theassessment 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 ADMEproperties of drug candidates prior to performing in-vivo studies, most likely reducing development costs anddecreasing the number of failures related to the ADME properties of drugs,"Benet adds.
Another next step, Huang says, may well be an FDA collaboration todetermine how nutraceuticals interact in the liver with prescription andover-the-counter drugs to provide data that could be important to proposingregulations.
