In vitro drug interaction data critical in drug repurposing

Listen to this article on the DDW Podcast: In the wake of Covid-19 interest in repurposing a drug for a different indication to the one it was developed for has been high. Madison Knapp, Marketing Communications Specialist, and Dr. Brian Ogilvie, Vice President of Scientific Consulting, SEKISUI XenoTech offer insight into the process. In November 2020, 696 drug candidates filled the drug development pipeline for a single disease indication—Covid-19, driven by a coronavirus known as SARS-CoV-211. How were there so many hopefuls, less than a year after the virus arose, when a new chemical entity typically takes multiple years to be developed? The answer lies in a practice that saves drug developers time and money by allowing them to take an existing de-risked compound and apply it to a new indication. Repurposing (repositioning, re-profiling, or re-tasking) a drug potentially saves years of costly testing from going to waste, potentially providing a higher chance of success. “Perhaps most importantly, the risk of failure is lower because the repurposed drug has already been found to be sufficiently safe in preclinical models and humans if early-stage trials have been completed, it is less likely to fail at least from a safety point of view in subsequent efficacy trials.".2 Examples of this include the attention-deficit/hyperactivity disorder (ADHD) medication Strattera (atomoxetine) which went through the development pipeline first as a selective norepinephrine reuptake inhibitor (SNRI) to treat depression and Parkinson’s disease (PD). In clinical trials research concluded that “Atomoxetine treatment was not efficacious for the treatment of clinically significant depressive symptoms in PD but was associated with improvement in global cognitive performance and daytime sleepiness.”.3 Atomoxetine re-entered the ring—this time for attention-deficit disorder— as the first nonstimulant medication for ADHD. Other repurposed drugs include Viagra (sildenafil) which was originally developed to treat hypertension and angina. Current regulatory policies encourage pharmaceutical companies to consider this option where possible. In its 2017 presentation, “Yes, you can teach an old drug new tricks: Regulatory Pathway for Repurposed Drugs,” the FDA highlights the advantages to re-tasking, citing risk mitigation, speedy market entry, and reduced cost.4. There is also a huge pharmacopoeia of drugs which have failed due to lack of efficacy, but usually this attrition occurs only after a full complement of preclinical safety testing which shows that a drug will be safe for administration to humans. If a sponsor elects to take one of these drugs and reposition it for a new indication, efficacy for the previous indication is often irrelevant. The drug is no longer a failure but a safe drug that hasn’t yet been tested for efficacy against the new indication. This means the drug developer can forego much of the preclinical work a new chemical entity would require. However, before a data package is submitted for regulatory approval to engage in clinical phases, an examination of existing data is necessary to ensure risk assessments and safety data is able to withstand current regulatory scrutiny—even if the drug was previously approved for market. The world of drug safety constantly evolves, so there are checkboxes that drug developers must consider now that may not have been on the list five years ago. This is true for evaluation areas such as drug-drug interaction (DDI) risk, where there have been guidance updates to reflect latest scientific consensus. This review process can be complex and requires familiarity with updated guidance, how it may have changed since the drug was originally approved for Investigational New Drug (IND), and expertise in using testing and data to understand a compound’s risk profile. Reviewing preexisting data: gap analysis Sometimes the need for a treatment necessitates fast-tracking a compound through development checkpoints to get to clinical phases quickly. Urgency should not mean sacrificing due diligence. In repurposing drugs for a new indication, a critical part of the process is to review data about the drug’s safety and ensure there are no ‘gaps’ which could cause safety issues for clinical trial volunteers or patients. Gap analysis, with the assistance of an expert familiar with drug-drug interaction (DDI) studies from a regulatory and a scientific perspective, can prove invaluable. It helps paint an accurate picture of risk for a sponsor that could inform crucial decisions in the clinic and explain results that would otherwise cause roadblocks for getting through clinical stages. Evaluating your drug’s risk of DDI The best approach drug developers can use to anticipate potential DDI issues in the clinic is through nonclinical in vitro studies to determine a drug’s perpetrator or victim potential in a transporter- or metabolism-mediated DDI. Sufficient in vitro DDI investigation prevents unnecessary exclusion of patients from clinical trials and informs clinical DDI study design if appropriate. With appropriate DDI risk assessment, regulators and drug developers alike can be more confident in the safety of potential therapies. Several standard in vitro DDI studies can predict a compound’s likelihood to cause drug-drug interactions via inhibition and induction of drug-metabolising enzymes or drug transporters or their activities. Investigating drug metabolism-mediated interactions Inhibition assays predict a compound’s perpetrator potential by measuring inhibition of significant drug-metabolising enzymes like cytochrome P450 (CYP) or UDP glucuronyltransferase (UGT). The consequential reduced metabolism of a victim drug could potentially lead to toxicity due to increased parent drug concentrations in plasma. In contrast, induction studies are used to measure potential of the compound to up-regulate drug-metabolising enzymes. The resulting increased rate of clearance for a victim drug could lead to reduced efficacy. Investigating drug transporter-mediated interactions Drug transporters, the proteins that deliver the compound to and from the drug metabolising enzymes, are important to evaluate. In vitro drug transport studies are additive in assessment of DDI potential by providing information on a compound’s substrate potential and likelihood to inhibit transporters which may be key in another drug’s clearance. The FDA’s 2020 final guidance for in vitro DDI studies asserts that, “coupled with appropriate in vitro-in vivo extrapolation methods these assays can determine if the sponsor should conduct an in vivo drug interaction study.” Completing your compound’s ADME profile To have meaningful results from core DDI studies, several fundamental ADME data can provide preliminary information and/or context for DDI study outcomes. For example, the 2020 FDA guidance highlights importance of using ADME studies to inform drug transport study design, stating that drug transporters included in substrate potential studies “should be evaluated based on ADME data.” Basic drug metabolism studies sponsors should include are etabolic stability, metabolite characterisation, and reaction phenotyping. Metabolic stability screening in hepatocytes or subcellular fractions (such as microsomes or S9 fraction) first determines a drug’s ability to be converted to metabolites by measuring the rate of intrinsic clearance by drug-metabolising enzymes. Metabolite characterisation and identification studies allow a drug developer to find out which metabolites may be formed from the parent drug and if any are unique to humans or disproportionately higher in human than preclinical animal models. Qualitative metabolic profiles, and proposed biotransformation schemes are established in each species as well to determine which will be most similar to a drug’s metabolism in a human. Comparing metabolite formation in human and other species can help drug developers early in development choose an appropriate animal model (species) for definitive nonclinical studies. Reaction phenotyping provides insight into which cytochrome P450 (CYP) enzymes are responsible for the metabolism of a drug candidate and identifies its victim potential for metabolism-mediated DDIs. Definitive reaction phenotyping experiments often begin with a panel of recombinant human CYP enzymes to identify potential activity with specific CYP enzymes. Loss of parent drug or metabolite formation is measured and the rate of metabolism is determined. These data are then corroborated by incubation with human liver microsomes (HLM) and selective CYP inhibitors. Metabolism by non-CYP pathways can be detected as well, especially if hepatocytes are used, and can inform the need for follow-up studies. A cautionary tale In his 2019 webinar, drug metabolism expert Dr. Larry Wienkers warns of missteps when choosing to sideline investigations into drug metabolism as permitted by the ICH M3(R2) guideline in the case of life-threatening indications. “It’s sometimes seen as a kind of ‘get out of jail free’ card, so companies will forego certain investigations, shortchanging themselves in scholarship around metabolism, failing to understand routes of metabolism and they end up missing major metabolites that could cause very serious problems.”.5 Case studies examined to illustrate this point include aldehyde oxidase (AO)-metabolised drugs. A drug’s metabolism needs to be understood before a molecule enters the clinic to anticipate DDI risk restrictions and to identify active or human-specific metabolites. A recent example: DDI & Covid-19 “Given the rapid spread of Covid-19 and its relatively high mortality, filling the gap for coronavirus-specific drugs is urgent. Researchers, ethics boards, and regulators are accustomed to developing trial plans over months, not weeks—a time frame that is not afforded during this emergent situation. It is necessary for all involved to work faster and more efficiently and then position the well-justified drugs for registration-enabling trials during the next peak.”.6 As pharmaceutical companies seek effective treatments and vaccines for Covid-19, drug-drug interaction must be considered. If taking a drug saves someone’s life, then DDI risk is often outweighed by benefit and data such as these may be abbreviated, deferred, or omitted to make those drugs available quickly...7 Covid-19 cases range from mild symptoms to acute respiratory distress. As such, it will likely prove beneficial to have multiple treatment options, and DDI data could differentiate a good option for a patient from a more dangerous one. Many DDIs can be managed clinically if dosage adjustments can be made, but the potential must be identified through testing first. The University of Liverpool has created a database to map out evidence of DDI risk associated with known experimental treatments for Covid-19. Its analysis shows that some commonly prescribed medications including antiarrhythmics, beta blockers, anti-coagulants, calcium channel blockers, and statins may pose dangerous risks to clinical trial volunteers or future patients treated for Covid-19.8 It is vital that drug developers pay attention to DDI risk as an important component of their drug’s safety testing. Volume 22, Issue 2 – Spring 2021 Biography Madison Knapp is Marketing Communications Specialist at SEKISUI XenoTech. She creates scientific content related to products and services that help drug developers navigate challenges in drug metabolism and drug-drug interaction risk. Madison received her Bachelor of Science from the University of Missouri in 2015 and joined SEKISUI XenoTech in 2019. Dr. Brian Ogilvie is Vice President of Scientific Consulting at SEKISUI XenoTech, joining the company in 1997. He earned his Ph.D. in toxicology from the University of Kansas Medical Center and B.A. in molecular biology from William Jewell College. Dr. Ogilvie is a revered expert in drug interaction studies, having authored or coauthored over 50 topical scientific posters, peer-reviewed publications and book chapters. References Mikulic, M. “Number of coronavirus (COVID-19) drugs and vaccines in development worldwide as of November 26, 2020, by phase” November 2020 www.statista.com/statistics/1119060/coronavirus-drugs-in-development-by-phase-worldwide/ Pushpakom, Sudeep, et al. “Drug Repurposing: Progress, Challenges and Recommendations.” Nature Reviews Drug Discovery, vol. 18, no. 1, 2018, pp. 41–58., doi:10.1038/nrd.2018.168. Weintraub, D., et al. “Atomoxetine for Depression and Other Neuropsychiatric Symptoms in Parkinson Disease.” Neurology, vol. 75, no. 5, 2010, pp. 448–455., doi:10.1212/wnl.0b013e3181ebdd79. Karst, Phelps, McNamara. “Yes, You Can Teach an Old Drug New Tricks: Regulatory Pathway for Repurposed Drugs.” FDA Law Blog, March 2017. http://www.fdalawblog.net/wp-content/uploads/archives/docs/ASENT%20-%20Repurposing%20-%203-2017.pdf Gordon, David E., et al. “A SARS-CoV-2 Protein Interaction Map Reveals Targets for Drug Repurposing.” Nature, 2020, doi:10.1038/s41586-020-2286-9. Wienkers, Larry. “Drug Metabolism Related Safety Considerations in Drug Development.” Drug Metabolism Updates Seminar Series, 5 Dec. 2019. https://www.xenotech.com/scientific-resources/webinar-series/2019/drug-metabolism-related-safety-considerations Kiplin et al. “Rapid repurposing of drugs for COVID-19” Science 22 May 2020: Vol. 368, Issue 6493, pp. 829-830 DOI: 10.1126/science.abb9332 Page 2, ICH M3(R2) Guidance for Industry “Nonclinical Safety Studies for the Conduct of Human Clinical Trials and Marketing Authorization for Pharmaceuticals” 2010. https://www.fda.gov/media/71542/download. Accessed June 2020. J Pinkowski.“Drug-Drug Interactions Could Imperil COVID-19 Treatment” May 10, 2020 Medscape https://www.medscape.com/viewarticle/930265