Relevance of physicochemical properties and functional pharmacology data to predict the clinical safety profile of direct oral anticoagulants

Abstract

Direct oral anticoagulants (DOACs) have rapidly become the drug class of choice for anticoagulation therapy in secondary care. It is known that gastrointestinal hemorrhage are potential side effects of the DOAC drug class. In this study we have investigated the relevance of molecular structure and on/off‐target pharmacology as a predictor of adverse drug reactions (ADRs) for the DOAC drug class. Use of the Reaxys MedChem module allowed for data mining of all possible reported off‐target effects of the DOAC class members. For the first time, the MHRA Yellow card database in combination with prescribing rates in the United Kingdom (data for n = 30 566 936 DOAC Rx (up to 2017) and ADR data n = 22 275 (up to 2018)) were used for our data comparison of DOACs. From the underlying reported data, we were able to rank the DOACs in terms of the likely adverse events we would expect to observe. We identified potential risks of ADRs based on the DOACs pharmacology including the expected GI hemorrhage, but also the unexpected risk of stroke, pulmonary embolism and kidney injury. Statistically significant (P < .001) differences were found between all DOACs and their total number of ADRs. Although the risks are small, strong statistical correlation between observed pharmacology and national ADR data is observed in three out of the five areas of concern.

Direct oral anticoagulants for unusual‐site venous thromboembolism

“…In this context, dabigatran might be the preferred choice because of its lowest potential for crossing the blood-brain barrier, compared to the other DOACs. 110 However, more evidence is needed to understand whether these pharmacologic properties translate into different outcomes in clinical practice. Some contraindications to DOACs can also be identified among patients with CVT ( Figure 2).…”

“…Given their favorable safety profile, DOACs are a therapeutic option for selected patients with CVT, especially those with mild/moderate clinical manifestations. In this context, dabigatran might be the preferred choice because of its lowest potential for crossing the blood‐brain barrier, compared to the other DOACs 110 . However, more evidence is needed to understand whether these pharmacologic properties translate into different outcomes in clinical practice.…”

Polypharmacology of clinical sodium glucose co‐transport protein 2 inhibitors and relationship to suspected adverse drug reactions

“…The standardization of suspected ADR data to prescribing rate prevents misinterpretation of the raw values and has been applied in other pharmacovigilance studies. 29 , 31…”

“…Our continuing research interest in the intersection of medicinal chemistry 28 with clinical prescribing and associated ADRs 29 , 30 , 31 warranted an application of our techniques for understanding the potential links between the SGLT2i's polypharmacology and ADRs landscape. Furthermore, recent studies have revealed that drugs believed to be highly selective frequently address multiple target proteins 32 and this may affect SGLT2i performance 33 and could lead to a more stratified approach in clinical practice.…”

Voltammetric Behaviour of Drug Molecules as a Predictor of Metabolic Liabilities

“…Our interest in connecting the voltammetric behaviour of drug molecules to their biological properties is derived from our research into the electrochemistry of small molecules [12][13][14] and adverse drug reactions [15,16]. Recent disparate research has found connections between the redox behaviour of a drug and its biological potency [17][18][19] and the oxidation potential and toxicity of MDMA (Ecstasy) derivatives [20,21] and thiobenzamides [22], and voltammetric studies for assessing electrogenerated drug metabolisms [23] as well as a study of xeniobiotics in the environment [24].…”