Alongside the need for evidence that a drug works, regulatory bodies such as the Food and Drug Administration (FDA) must be sure that a compound is safe for patient use in a clinical setting.
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Among other chemistry, manufacturing, and biology standards, key components of a successful investigational new drug (IND) application include a robust pharmacokinetic (PK) profile, encompassing absorption, distribution, metabolism, and excretion (ADME), drug transporter activity, and the potential for pharmacokinetic-based drug-drug interactions (DDIs).
In vitro preclinical study timing
Historically, it was not possible to detect ADME problems until the IND application preparation stage, which often led to “serious disruption of the development process, and often resulted in closure of the project.”1
Regulatory agencies now expect drug developers to have thoroughly addressed all these components early in the development process, using early-stage testing to eliminate candidates that are unlikely to meet approval thresholds.
“In vitro studies are conducted early in the process to assess the investigational drug’s metabolism pathways. This knowledge helps inform whether a clinical drug-drug interaction study is needed. Many companies consider drug interaction liability when making a decision to move forward with an investigational drug. For example, if a compound is known to be susceptible to major drug interactions, the company might decide to de-prioritize that compound.”2
To comprehensively address all key aspects, sponsors should carefully evaluate which nonclinical studies are necessary to assess pharmacokinetic properties and drug-drug interaction (DDI) potential prior to clinical entry. Special attention should be given to both draft and final guidance documents published by regulatory authorities.
Regulatory guidance outlines recommendations for planning and conducting in vitro studies to determine DDI potential. This emphasizes the importance of examining potential interactions between a drug candidate and drug-metabolizing enzymes, assessing the likelihood of the candidate acting as a substrate or inhibitor of drug transporters, and evaluating the impact of the candidate’s metabolites on its safety and efficacy—all within a risk-based framework prior to IND submission.
While sponsors can address any gaps in their IND package or resolve DDI-related concerns during clinical trials, thoroughly exploring DDI and ADME parameters beforehand allows for more informed clinical study planning and may help avoid unexpected outcomes.
Early, comprehensive ADME improves chances of success
“Inadequate ADME properties can be devastating to otherwise good drug activity.”3
Previously, poor pharmacokinetic profiles were responsible for the failure of more than 40 % of drug candidates. However, since 1991, the drug development process has shifted toward earlier exploration of ADME/PK, enabling more effective candidate qualification through in silico and in vitro assays during the early stages of development.
This approach helps avoid the costly mistake of identifying pharmacokinetic issues later in the pipeline. By 2008, thanks to the efforts of scientists in the pharmaceutical industry and specialized ADME contract research organizations (CROs), this failure rate was reduced to less than 1 %.
This improvement was achieved through the development of better techniques, tools, and technologies that enable efficient in vitro ADME studies early in the process, helping validate strong candidates and eliminate weaker ones.
Lead to candidate (lead optimization)
BioIVT offers a range of drug metabolism, protein binding, and transporter studies designed to enable drug developers to rapidly acquire data for preliminary planning of definitive studies or comparison of multiple compounds.
There is significant value in understanding how a compound’s pharmacokinetic profile will perform in practice. For example, a drug developer may discover if a candidate is likely to fail at an early stage, but it may be possible to use that data to adjust the drug’s chemistry to optimize its PK prior to moving through more expensive development phases.
Candidate to IND (preclinical drug development)
Definitive in vitro and in vivo data is the cornerstone of clinical applications. Data packages should be comprehensive and contain all required information.
Drug developers are advised to consult current guidance for details on basic in vitro studies, but they should also perform additional studies where necessary, for example, to explore areas like inhibition, induction, drug transport, or metabolism.
Working alongside its partners at the Drug Development Solutions Center, BioIVT can provide in vivo ADME and PK studies designed to complement or provide additional observations to in vitro studies. These studies can also offer a different view of a drug’s disposition, such as a quantitative whole-body autoradiography (QWBA) study.
In vitro experiments provide useful data on activities at the cellular level, but an additional whole-system view can provide useful wider contextual information for in vitro data.
BioIVT can provide advice and guidance where definitive studies yield unexpected results. The company’s in-house experts have extensive knowledge on regulatory expectations inside and have a great deal of experience dealing with unanticipated outcomes from drug metabolism and drug interaction studies.
Each study performed at BioIVT benefits from the company’s signature consultative approach, and its team of expert consultants remains on hand to help make sense of challenging data and support clients to plan their next steps towards regulatory approval.
Post-IND and Pre-NDA
Development strategies can vary, and if a sponsor approaches late in development, support can still be provided to address gaps and prevent DDI-related attrition.
Occasionally, unexpected issues arise in the clinic that were not detected during preclinical development. In such cases, reaching out for assistance can make a significant difference.
In vitro and in vivo studies can supplement clinical trials to help better understand the drug candidate's behavior and, at times, clarify clinical outcomes. With flexible study designs and extensive expertise in pharmacokinetics, the right support can help close those gaps and ensure a safe and effective drug reaches the market.
References and further reading
- Czarnik, A.W., and H.-Y. Mei. “Strategy and Drug Research.” Medicinal Chemistry, 2nd ed., Elsevier Science, 2007, pp. 289–557.
- FDA “CDER Conversation: Evaluating the Risk of Drug-Drug Interactions” October 2017 https://www.fda.gov/drugs/news-events-human-drugs/cder-conversation-evaluating-risk-drug-drug-interactions
- Kenakin, Terry. “Pharmacokinetics I.” Pharmacology in Drug Discovery and Development, Second ed., Academic Press, 2016, pp. 157–191.
Acknowledgments
Produced from materials originally authored by Madison (Knapp) Esely-Kohlman from BioIVT.
About BioIVT
BioIVT, formerly BioreclamationIVT, is a leading global provider of high-quality biological specimens and value-added services. We specialize in control and disease state samples including human and animal tissues, cell products, blood and other biofluids. Our unmatched portfolio of clinical specimens directly supports precision medicine research and the effort to improve patient outcomes by coupling comprehensive clinical data with donor samples.
Our Research Services team works collaboratively with clients to provide in vitro hepatic modeling solutions. And as the world’s premier supplier of ADME-Tox model systems, including hepatocytes and subcellular fractions, BioIVT enables scientists to better understand the pharmacokinetics and drug metabolism of newly discovered compounds and the effects on disease processes. By combining our technical expertise, exceptional customer service, and unparalleled access to biological specimens, BioIVT serves the research community as a trusted partner in ELEVATING SCIENCE®.
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