Clinically Relevant Drug Transporters: What Progress is to be Expected in 2012?
Research into drug transporters forms an increasingly important part of the non-clinical development phase, with new fields such as pharmacogenomics offering new approaches to an area that is increasingly under the microscope of regulatory agencies.
Last year saw the publication of the International Transporter Consortium white paper on the issue, and the Food and Drug Administration is poised to release further guidance in the near future.
The ITC report provided an overview of the key transporters involved in drug absorption, giving examples of how technology has been used in studies of transporter-related drug-drug interactions and criteria for clinical studies into these interactions.
Drug-drug interactions are gaining a greater amount of attention across the industry and is a trend which is set to continue into 2012 and beyond, as the population ages and people take a greater number of different drugs.
Major drug-drug interactions have been present in a number of drugs pulled in the US for safety reasons in recent years.
With new FDA guidance set to take its cues from the ITC report, recommendations on study designs and model decision trees are likely to feature more heavily in the future.
The ITC's report in particular sought to highlight the need for a better understanding of the interplay of drug-metabolising enzymes and transporters in the disposition of new molecular entities (NMEs) to improve the production of drug-drug interactions.
According to a review of the report in Nature, understanding of NMEs to this effect will be critically important to their labelling and safe and effective use. Due to the quickly evolving nature of transporter research, pre-marketing applications do not always include transporter-specific information at present.
"The FDA has recently asked for post-marketing studies of potential transporter-mediated drug–drug interactions.
"A review of recent post-marketing commitment (PMC) and post-marketing requirement (PMR) reports indicated that more than a quarter of the clinical pharmacology PMC and PMR reports were related to drug–drug interactions," the authors Shiew-Mei Huang and Janet Woodcock noted.
This is just one of the new requirements the pharmaceutical company has to meet in the field of drug-drug interactions, with many more expected for the future.
Global Industry Analysts predicted in its most recent report on ADME toxicology testing that transporter proteins, which form an increasingly important part of such assessments, will also form "a part of regulatory standards for new drug applications."
This is a trend which is being reflected across the industry.
US-based Absorption Systems recently received a European patent for its novel Breast Cancer Resistance Protein (BCRP) knockdown cell line, for the prediction of drug-drug interactions from drug transporters.
Previous research suggested as many as 4 percent of older Americans are at risk of a major DDI, simply due to a lack of awareness of the impact of the drug combinations.
The company's CellPort system uses an opposite method to older models. Rather than overexpressing the transporter of interest, in this case BCRP, the system knocks down one transporter at a time, so each phenotype is long lasting.
A process of elimination is then used to determine if a drug interacts with a specific transporter.
CellPort was used earlier this year in a study conducted in collaboration with the FDA to assess the drug transporters responsible for eliminating statins from the body, aiding in the future identification of potential DDIs before they occur.
Covance is another player touting new service offerings this year. It expanded its drug metabolism services to include drug-transporter interactions with eight human transporters. The eight cell lines stabley express P-gp/MDR1, BCRP, OCT1 & OCT2, OAT3, OATP1B1 & OATP1B3, and MRP2.
The future of innovative drug transporters is also being cemented through start-ups gaining the funding needed to launch their platforms onto the market.
DLVR Therapeutics recently received $2 million in cash and in-kind support from a round of funding, which will enable it to move forward with its plans for moving its chemotherapy delivery system towards a pre-clinical regulatory package and continue development of its small interfering RNA (siRNA) program.
Among those investing in the project are the University Health Network (UHN) and the Ontario Institute for Cancer Research.
Frank Gleeson, president and chief executive officer of DLVR, said: "This additional financing highlights the significant potential of our nanoparticle delivery platform approach.
"Our nanoparticles offer a unique and selective delivery of the payload to the cytosol of the intended target reducing undesired side effects. MaRS Innovation has recognised this great potential and its investment enables us to accelerate our efforts to advance a chemotherapeutic candidate into IND-enabling studies."
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