It’s clear that in vitro transporter investigations are key to approvability, but they can also provide valuable predictions and insight into clinical outcomes – something we at Absorption Systems call ‘translatability.’
I understand that drug developers desire the most streamlined path, and that in vitro transporter investigation (including a panel of at least seven transporters) may seem like a roadblock or obligation. But these in vitro tests (when performed correctly) are actually an important investment in the future of your compound. Under appropriate conditions and using validated test systems, one may gain a more complete picture of drug absorption, distribution, metabolism, and excretion (ADME) from knowledge of transporter interactions.
In addition to guiding clinical strategies, it may also be possible to waive clinical studies. The FDA formally recognizes the consideration of drug-specific properties in the new Guidance which states that, “for drugs that are highly permeable and highly soluble, the intestinal absorption is not a rate-limiting step, and, therefore it may be appropriate to exempt such drugs from the in vivo evaluation with a P-gp or BCRP inhibitor.” In other words, if a drug has high absorption (>90%), its AUC couldn’t possibly be elevated more than ~10% by a co-dosed inhibitor of intestinal P-gp or BCRP, thereby eliminating the possibility of a drug-drug interaction involving intestinal absorption. Absorption Systems is the only CRO that offers a validated Caco-2 test system for both transporter interaction and BCS classification, enabling potential biowaivers.
Continuing the phone conversation begun in my previous blog post, I sense relief, maybe even delight, in the scientist’s voice as she realizes what a powerful tool in vitro testing can be. At the ITC2 workshop, Dr. Shiew-Mei Huang stressed that, in many cases, in vitro is more reliable than in vivo testing. She presented clinical data for midazolam co-dosed with ritonavir or ketoconazole and the wide variability in AUC changes (4- to 10-fold or 8- to 16-fold, respectively), begging the question, “is clinical data really the truth?” With increasing reliance on in vitro tools, there is an ongoing effort from regulatory agencies to consolidate “best practices” related to transporter assays. This is also a long-held passion of Absorption Systems.
“I understand that I should do this in vitro and do it early. But which test system do I use?” I empathize with the scientist − when it comes to transporters, there is a plethora of available test systems and assay formats. This is a common dilemma faced by scientists in the industry, and Absorption Systems’ goal is to simplify the process as much as possible. Some of the most important considerations include:
- Human vs. non-human test systems (relevant targets)
- Cell-based vs. subcellular models (multiplicity of transporters and their interplay)
- Over-expressed vs. knockdown test systems (potential for exaggerated response)
- Probe substrates (clinical relevance)
- Chemical inhibitors (lack of specificity)
- Identifying and taking advantage of drug-specific factors (enabling biowaivers)
- Protocol optimization for maximum ‘translatability’ (selection of therapeutically relevant concentrations, considering solubility, non-specific binding, etc.)
“OK, I’m starting to see the light. Thanks!” The scientist appreciates the value of working with a provider that considers experimental nuances in designing in vitro transporter interaction studies. Now, let’s talk! (610-280-1496)