There has been a reluctance for modern drug discovery programs to consider covalent inhibitors due to toxicity concerns. An important contributor has been the drug toxicities of several high-profile drugs believed to be caused by metabolic activation of reversible drugs.  For example, high dose acetaminophen can lead to the formation of the reactive metabolite N-acetyl-p-benzoquinone imine.  Also, covalent inhibitors such as beta lactam antibiotics which contain weak electrophiles can lead to idiosyncratic toxicities (IDT) in some patients. It has been noted that many approved covalent inhibitors have been used safely for decades with no observed idiosyncratic toxicity. Also, that IDTs are not limited to proteins with a covalent mechanism of action.  A recent analysis has noted that the risk of idiosyncratic toxicities may be mitigated through lower doses of administered drug.  Doses of less than 10 mg per day rarely lead to IDT irrespective of the drug mechanism.