What makes a scientific conference great? New, cutting-edge data from experts in the field, to be sure. To me, it’s equally important to have lively, stimulating, insightful discussion after the oral presentations; this is extremely rare, but it really helps illuminate the presentations and put them in perspective. I’ve come to expect both from the annual International Conference on Drug-Drug Interactions (DDIs) in Seattle, presented by the Institute for Scientific Communications, and this year’s edition (the 14th) was no exception. It’s not a large meeting by any means (~125 attendees), but apparently the optimal size for productive give-and-take.
DDI-2011 brought together leading experts from industry and academia in various aspects of drug-drug interactions. Many of the faces were familiar, as they attend this conference every year. Others were new, and they presented what were for me some of the most interesting results. Several people who were supposed to be at the conference were at an invitation-only meeting at the FDA to finalize the draft guidance on DDI testing. One recommendation will reportedly be the use of cryopreserved, rather than fresh, hepatocytes (the advantages presumably being pre-characterization and the ability to use the same batch over time with multiple test compounds).
If a clinical perspective on DDIs is your thing, you would have enjoyed the annual review of the DDI literature. Two clinical observations of note: the AUC of aliskiren is elevated 6.5-fold when co-administered with itraconazole, apparently due to inhibition of P-gp in the gut; a component of apple juice and orange juice inhibits gut OATPs, which decreases the exposure of many drugs, including atenolol, celiprolol, ciprofloxacin, fexofenadine, and pravastatin. Two different speakers discussed the fact that circulating metabolites of drugs frequently contribute to DDIs but are seldom evaluated in pre-clinical studies.
If you’re into preclinical prediction of DDI risk, there was plenty of information for you as well. Rheem Totah (University of Washington) thoroughly covered CYP2J2, an enzyme that is expressed in liver, intestine, and kidney, but at especially high levels in cardiac myocytes. Most CYP2J2 substrates are also metabolized by CYP3A4, often at the same position. And all of the most potent inhibitors of CYP2J2 cause QT prolongation and inhibit hERG, which raises the question of the role of CYP2J2 in QT prolongation. N.L. Simmons (University of Newcastle upon Tyne, UK) presented some compelling data on P-gp induction in human intestinal T84 cells. I was evidently not alone in my ignorance of the fact that digoxin, a P-gp substrate, also induces expression of the transporter.
If you’ve ever evaluated CYP induction in human hepatocytes, you know that sometimes a compound will be scored positive in some donors and negative in others. According to the results of a PhRMA survey of CYP induction practices in the industry, (i) if a compound is a CYP inducer in even one donor (but not in others) it should be considered an inducer, and (ii) if you only measure one endpoint, it should be mRNA.
Finally, have you ever observed apparent stimulation of transporter activity at low concentrations of a compound that is an inhibitor at higher concentrations? We have, although we didn’t know what to make of it. Similar observations (apparent allosteric modulation) were reported by two speakers, including a possible connection to cholestasis in the clinic for modulators of MRP2 in the liver.
You can be sure that Absorption Systems will continue to stay on top of cutting-edge research in DDIs and related fields, both by actively participating in conferences like this one and by presenting the results of our own research, as we often do.