Tag Archives: Safety Intelligence Program

Strength in numbers: more is better for drug safety/risk prediction

Posted on by
Reply

The re-use of data is an ever present issue within the pharmaceutical industry.  Publicly available data is an important resource for companies looking to develop new drugs, and find new uses for current ones.  The search has just become easier with the publication of the DrugMatrix database by the National Toxicology Program.

DrugMatrix is a large molecular toxicology reference database and informatics system. It contains data on the effects of more than 600 therapeutic, industrial and environment chemicals at a variety of doses and exposure times. For each of these compounds, relevant data curated from the literature is available, as well as assay results for inhibition of 132 protein targets. These have been chosen for their importance in drug development, and so among them, we can find drug-metabolizing enzymes or proteins involved in important toxicities.

The core of DrugMatrix is a set of highly standardised toxicological experiments performed in male, Sprague-Dawley rats, resulting in a wealth of data regarding histopathology, clinical chemistry and gene expression responses elicited by 638 compounds. The main strength of this database is that it provides the basis to linking macroscopic observations to alterations in genetic pathways. And the great news is, Safety Intelligence Program (SIP) users can now access this fantastic resource, with the addition of ~88,000 curated assertions with DrugMatrix evidence. The inclusion of the DrugMatrix data in SIP makes it possible to answer questions that were currently not addressable through the DrugMatrix interface, as the data is now integrated with knowledge extracted from several other relevant sources such as Medline, DailyMed and FDA NDAs.

dmblog1

DrugMatrix interface showing the results of an experiment where the administration of 2mg/kg Cisplatin for 3 days caused a 1.4-fold increase in blood urea nitrogen.

To give an example, let’s look at the effects of Cisplatin in rats. According to DrugMatrix, this compound increases blood urea nitrogen level, which is an important safety signal because it is an indicator of renal health. If the kidneys are not working properly and the glomerular filtration rate decreases, blood urea nitrogen will increase. This compound level can also be associated with heart failure, dehydration, fever or high-protein diet.

dmblog2

SIP ToxPath knowledgebase summary matrix showing that Cisplatin-induced increases in blood urea nitrogen occur in different species and relevant datasources

The next thing we might be interested in knowing is whether the effect is replicated in other animal species. While DrugMatrix only includes rat information, a quick search in SIP will point to the answer. Firstly, we will see that apart from DrugMatrix, there are Medline records describing the same observation in Sprague-Dawley and Fischer 344 strains. Increases in blood urea nitrogen are also described in mouse and rabbit. More importantly, this finding is also seen in humans according to DailyMed and the Electronic Medicines Compendium.

But should we worry about kidney function because of this increase? We can search SIP to see if Cisplatin is known to be associated with kidney dysfunction in patients. Again, we can see that Cisplatin is linked to liver disorder-related biomedical observations in 43 assertions from 6 different datasources. This makes sense, as Cisplatin is a well-known nephrotoxicant and kidney toxicity is dose-limiting in this type of chemotherapy.

dmblog4

Summary matrix of associations between Cisplatin and kidney disorder in humans, and the sources where the data has been obtained from.

Finally, we might also be interested in assessing whether compounds that cause an increase in blood urea nitrogen share a similar structure or protein target. While DrugMatrix is an excellent tool for this task, it only queries the 600+ compounds that are included in the dataset. Conversely, at present, SIP contains 85,996 compounds and 22,036 proteins, which are part of 2,574,454 assertions, and this allows the users to expand the search and increases the likelihood of finding meaningful results.

This is a very good example that when it comes to toxicology and pathology data, there is certainly strength in numbers, and when two powerful tools such as these are put together, their usefulness is greatly enhanced.

A small subset of curated SIP assertions linking Cisplatin to kidney disorder in humans.

A small subset of curated SIP assertions linking Cisplatin to kidney disorder in humans.

How do you define a New Chemical Entity?

Posted on by
Reply

What’s the definition of a New Chemical Entity? A new chemical entity (NCE) is, according to the U.S. Food and Drug Administration, a drug that contains no active moiety that has been approved by the FDA in any other application submitted under section 505(b) of the Federal Food, Drug, and Cosmetic Act. This might seem pretty straightforward, but Keryx are currently finding that there are issues. Keryx (as you may have read in the news feeds) are having worries over the potential exclusivity of their new drug, Zerenex, as the active ingredient may not be distinct enough from Otsuka’s FerriSeltz, approved more than 15 years ago (according to IPD Analytics) – and this piqued my curiosity.

So, what is the definition of an “active moiety”?  Again, from the FDA website: “An active moiety means the molecule or ion, excluding those appended portions of the molecule that cause the drug to be an ester, salt (including a salt with hydrogen or coordination bonds), or other noncovalent derivative (such as a complex, chelate, or clathrate) of the molecule, responsible for the physiological or pharmacological action of the drug substance.”  Let’s look at the two compounds that are under scrutiny.

Zerenex_FerriSeltz

Fig 1: 2D chemical images of Zerenex and FerriSeltz active ingredients

Zerenex_FerriSeltz_BMO_matrix

Fig 2: Summary matrix from SIP ToxPath knowledgebase, of associations between either FerriSeltz (ferric ammonium citrate) or Zerenex (ferric citrate) and biomedical observations, systematically extracted from Medline, regulatory documents, and public domain toxicology databases, and formatted into assertional metadata, for rapid search and analysis.

If you look at the structures (Fig.1), you can see the potential similarity. However, the two indications are very different – FerriSeltz was approved for upper gastrointestinal enhancement during MRI;  Zerenex aims to lower blood levels of phosphorous in patients undergoing kidney dialysis. The two compounds also have quite different biological “fingerprints” (Fig 2), looking at the range of effects on various biomedical observations, reported across current and historic key public domain data sources. Looking at the tissue effects of the two active ingredients again gives a different summary matrix (data not shown).  For example, from the biological effects matrix, it can be seen that there are only a few effects that both compounds have in common (effects on ferritin biosynthesis, iron level, oxidative stress) and many effects where there is no overlap (e.g. ALT and AST levels). These data provide more insight into the two different compounds, and hint to possible paths for further investigations.

Meanwhile, I await with interest the outcome of the FDA deliberations – as I am sure, so do Keryx.

SIP ToxPathkb for Pharmacovigilance intelligence

Posted on by
Reply

OmniViz CoMet analysis, showing concordance of compound clusters (by structure) with particular patient adverse events or pathologies (using MedDRA level 2 terminology). From this structure–activity relationship view, it can be seen that certain clusters are over-associated with particular effects (e.g. Cluster 13 for adrenal and endocrine effects) or under-associated (e.g. Cluster 2 and cell metabolism disorders).
Note: The +1 to -1 scale shows how much the concordance deviates from the expected value; thus the more positive the value the greater is the enrichment.

A key part of clinical and pre-clinical development is using the knowledge all around us, on what is known about compounds that cause particular adverse events, what are the underlying mechanisms of key pathologies seen in studies, or whether targeting a particular protein will increase the likelihood of side effects.  Since Instem bought BioWisdom, we have been working on ensuring that the Safety Intelligence Program (SIP) can provide the best source of ToxPath reference knowledge, both increasing the in-depth intelligence for specific tissues, ensuring that the broad coverage is maintained, and increasing the reference data for compound-protein associations.

Following requests from customers, we have recently increased our data sources for pharmacovigilance, and you can now search SIP for adverse event data from:

Potential Signals of Serious Risks/New Safety Information Identified from the FDA Adverse Event Reporting System

  • These reports are FDA summaries for any potential signals of serious risks/new safety information that were identified using the FDA AERS database during a particular quarter.

MHRA Drug Safety Updates

  • Monthly updates from the UK Medicines and Healthcare products Regulatory Agency (MHRA), to support the safer use of medicine.

WHO Pharmaceuticals Newsletter

  • A Newsletter (published 6 times per year) to disseminate information on the safety and efficacy of pharmaceutical products, based on information received from the WHO network of “drug information officers” and other sources such as specialized bulletins and journals.

This is in addition to the current integrated data from FDA AERS and FDA MedWatch.  These data sources, combined and harmonised with literature data from PubMed and many other sources, provide access to valuable data stretching back to 1960s, for adverse drug reactions in patients.  This gives our SIP ToxPathkb users the potential to gain insights into the post-market safety of drugs.

New liver intelligence in Instem’s Safety Intelligence Program

Posted on by
Reply

The liver is an important indicator of drug toxicity.  It deals with toxins and many medicinal products that pass through the body, and as such, has a high chance of being exposed to drug toxicity.  More than 900 drugs, toxins and herbs are known to cause liver injury1. Hepatic injury is a common reason for drug withdrawal, but can be difficult to detect as many drugs only cause it infrequently2.

The Safety Intelligence Program (SIP) is a knowledgebase of comprehensive intelligence, built from a wide set of public domain sources, around compounds causing adverse effects in tissues, including effects on biomarkers of tissue injury and also molecular mechanisms.

The data in SIP can be accessed via both drug class and chemical structure searches, meaning that drugs with similar structures and other properties can be compared to a drug in development.  This means that potential hepatotoxicity could be detected earlier in the drug development process, which could potentially lead to large savings.

Read more about New liver intelligence in Instem’s Safety Intelligence Program »→

Instem Scientific’s Safety Intelligence Programme (SIP) now contains in-depth coverage of adverse effects on skin

Posted on by
Reply

SIP is a knowledgebase of toxicological and pathological adverse effects of drugs and other compounds.  It contains deep coverage of biomedical observations (BMOs) occurring in many different tissues (e.g. liver, heart), and we can now add skin (including appendages such as hair and nail) to that list.

The skin is an important organ, being the largest in the body, and is affected by a wide variety of different drugs, including those administered topically and subcutaneously as well as via other routes.

Read more about Instem Scientific’s Safety Intelligence Programme (SIP) now contains in-depth... »→