Beyond the need for evidence that a drug works, Food and Drug Administration (FDA) and other regulatory bodies around the world need to see that a compound will be safe to give to patients in a clinical setting. Among other chemistry, manufacturing, and biology standards, key components of a successful investigational new drug (IND) or equivalent application include a sound pharmacokinetic (PK) profile encompassing ADME properties (absorption, distribution, metabolism, and excretion), drug transporter activity, and pharmacokinetic-based drug-drug interaction (DDI) potential.
Historically, ADME problems weren’t detected until IND application preparation, creating “serious disruption of the development process, and often resulted in closure of the project.”1 Regulatory agencies now expect drug developers to have crossed their T’s for all these components early on and to use early testing to weed out candidates that would not meet thresholds in the approval process:
“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 adequately cover all the bases, sponsors should carefully consider which nonclinical studies are necessary to evaluate pharmacokinetic properties and DDI potential before entry to the clinic and pay special attention to draft and final guidance for industry published by regulatory authorities. The most recent final guidance, published by FDA in January 2020, describes current recommendations for drug developers to plan and evaluate in vitro studies to determine DDI potential based on current scientific understanding, in harmony with the European Medicines Agency (EMA) and Japan’s Pharmaceutical and Medical Devices Agency (PMDA).
In this guidance, FDA highlights examination of potential interaction between a drug candidate and drug-metabolizing enzymes, potential of a drug candidate to act as a substrate or inhibitor of drug transporters, and potential impact of a drug candidate’s metabolites on the drug’s safety and efficacy using a risk-based approach, all prior to IND submission.3 If there are holes in an IND package or DDI-related concerns in the clinic, a sponsor could go back and conduct these studies in tandem with clinical trials; however, adequately exploring DDI and ADME parameters before IND may allow more informed planning of clinical studies and could prevent unexpected outcomes.
Do your ADME earlier.
“Inadequate ADME properties can be devastating to otherwise good drug activity.”4
It used to be true that poor pharmacokinetic profiles sank more than 40% of drug candidates, but since 1991 drug development has shifted exploration of ADME/PK to be earlier in the pipeline for more effective qualification of candidates via in silico and in vitro assays at early stages of development, avoiding the expensive mistake of finding pharmacokinetic problems later in the pipeline.3 Many scientists in the pharmaceutical industry and specialty ADME contract research organizations (CROs) have worked hard to bring that percentage down to <1% by 20084 by improving techniques, tools, and technologies to efficiently perform in vitro ADME studies early in development to validate strong candidates and weed out weak ones.
Lead to candidate (lead optimization)
We offer medium-throughput drug metabolism, protein binding, and transporter studies to help drug developers obtain data quickly for comparison of multiple compounds or preliminary planning of definitive studies. Getting a good sense of how a compound’s pharmacokinetic profile will shape up can be of enormous value—not only may a drug developer find out early if a candidate is likely to fail, but they can sometimes use that data to make decisions for adjustments to the drug’s chemistry to optimize its PK before it proceeds through more expensive development phases.
Candidate to IND (preclinical drug development)
Definitive in vitro and in vivo data make or break an application to the clinic. In order to have an air-tight data package, drug developers should consult current guidance for recommended basic in vitro studies but also should follow up with studies to explore inhibition, induction, drug transport, metabolism, or other areas if necessary. If there are unexpected results from definitive studies and you’re not sure where to turn—we can help. Our in-house experts know regulatory expectations inside and out and have “seen the weird stuff” when it comes to drug metabolism and drug interaction studies. Each study conducted at SEKISUI XenoTech comes with our signature consultative approach, and we also have a team of expert consultants on hand to help make sense of tricky data and can help you plan next steps towards regulatory approval.
Post-IND / pre-NDA
Development strategies can be variable, if you come to us late in development we can help you fill in the gaps to avoid PK-related failure. Sometimes, unexpected things happen in the clinic that may not have been caught during preclinical development. When this happens, give us a call. In vitro and in vivo studies can supplement clinical studies to better understand what’s happening with a drug candidate and can sometimes be used to explain clinical results. Our flexible study designs and deep knowledge of pharmacokinetics could be just what you need to fill in the gaps and bring a safe, effective drug to the market.
Learn more about:
 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 FDA “Guidance for Industry: In Vitro Drug Interaction Studies—Cytochrome P450 Enzyme- and Transporter-Mediated Drug Interactions” (final guidance) January 2020. Center for Drug Evaluation and Research., FDA, Silver Spring, MD. Kenakin, Terry. “Pharmacokinetics I.” Pharmacology in Drug Discovery and Development, Second ed., Academic Press, 2016, pp. 157–191.
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