Pre-clinical drug-drug interaction (DDI) assessment using in-vivo animal models along with in-vitro human systems based assays, aids in early prediction of clinical interactions possibilities and may help to prevent late phase failure of drug in clinic.
But DMEs and transporters of animals vary remarkably from humans, thus limiting their use for clinical predictions. Owing to these limitations "humanized" animal models are developed, which serves as a better model for prediction of metabolism and potential DDI in humans.
Apart from these humanized animal models what are other pre-clinical novel methodologies which are used for investigating/ predicting clinical DDI?
I'm not aware of any methodologies I would necessarily call novel, however, there are many methods other than humanized animal models that are used. The closest method to being novel that I'm aware of is in silico. Specifically, the software SimCYP which attempts to predict PK based on compound structure. In so doing it also provides information about which transporters and metabolizing enzymes are most likely involved. Using this information you can then make an informed guess about what drugs would likely cause a DDI so that you can better guide subsequent in-vitro testing. This software has been available for a number of years and continues to get better.
There are also a number of in-vitro methodologies such as using human liver microsomes and doing co-incubations with known metabolizing enzyme inhibitors and inducers. Such systems, however, often over predict interactions due to metabolism because there is no cell membrane through which your compound must pass, unlike an intact liver. Along the same lines, there are cell lines transfected with a single or panel of metabolizing enzyme so you can create a metabolism panel. Again, you can use co-incubations. Either of these options require a reasonable amount of additional work in categorizing the actual enzyme/transporter expression levels if you want to use it for allometric scaling.
As for assessing transport, you can always do trans-well assays with epithelial cells, but again you need to categorize the system quite well for allometric scaling. These are all common techniques used in high throughput screening and subsequent pre-clinical testing. There are many many more methods, however, most of them involve these primary techniques or modifications thereof. I hope this helps!
-Zack
Pre-clinical drug-drug interactions (DDI) assessment using in-vivo animal models especially the pharmacokinetics interactions. Its very important to detect the effect of NSAIs anti-inflammatory on the pk of antibacterials when concurrently used together in some acute infections, or the effect of lead intoxication on the kinetics of sulphonamides or antibacterials.I think this pre- clinical trials is very benefit for monitoring the dose & frequency of administration swell as the duration of treatment,
Dear Swati,
Greetings from Swapnil..!!!
Invitro tools and tech. are widely used along with Invivo and then Insilico to confirm the molecular mechanism of DI, HDI (Herb drug interactions)
Please find attached USFDA document about the same and i hope it will solve ur most of the doubts.
Secondly, you can use also use the IdMOC tech. which is not mentioned in draft guidance. (see Li AP. Critical Human Hepatocyte-Based In Vitro Assays for the Evaluation of Adverse Drug Effects. Drug Discovery and Development – Present and Future. 151-168.)
If you want any kind of information regarding DMPK, PK-PD, DI and HDI, I'll be happy to provide you promptly ....
Best regards,
Swapnil.
@ Swapnil Borse: Do you have a pdf file of 'Critical Human Hepatocyte-Based In Vitro Assays for the Evaluation of Adverse Drug Effects. Drug Discovery and Development – Present and Future' ? If you have, could you please upload it. Thanks
@AKM Mahmudul Haque, Dear Its freely available : http://cdn.intechopen.com/pdfs-wm/25226.pdf
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