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On-target toxicity is often also called mechanism-based toxicity because the on-target action of a drug is the same as its mechanism of action. On-target toxicity normally arises from two different situations. First, the response from target binding must be held within a window and too great of an effect leads to a safety risk. Second, targets can often be associated with multiple response pathways, and maybe one of the other associated responses leads to toxicity. The illustration at the bottom of the slide highlights both of these possibilities. Here is a generic target, likely an enzyme or receptor. Let’s say that our goal is modulate this target with a drug to reduce blood pressure. If a patient has high blood pressure, then reducing blood pressure is good. But, you don’t want to reduce blood pressure too much because that could be dangerous. So, this is like type #1. We want a response, but not too great of a response. Let’s assume that our target also exerts some control over the patient’s heart rate. That’s a potential problem. In order to affect blood pressure, we will necessarily impact heart rate because of the nature of the drug target. Sometimes selection of a different target can avoid on-target toxicity of type #2, but type #1 toxicity is often unavoidable.
In the early-1900s, arthritis pain was a growing unmet medical need and often a debilitating problem. In the mid-1900s, steroids, namely hydrocortisone and closely related compounds, were found to have anti-inflammatory activity to treat arthritis pain. As these compounds became more available, they were widely prescribed to manage arthritis pain. The target (one of the targets) bound by hydrocortisone is the glucocorticoid receptor, which is a nuclear receptor. The glucocorticoid receptor affects gene expression in the nucleus, and the genes affected are linked with inflammation, immune response, and mood. Patients taking hydrocortisone for arthritis pain do sometimes report odd mood changes, and this is a form of on-target toxicity. Candidly, while hydrocortisone does demonstrate on-target toxicity, hydrocortisone’s off-target toxicity on the mineralicortocoid receptor poses the more problematics risks to patients. Today, steroids are less often used today for arthritis pain. They were replaced with NSAIDs – non-steroidal anti-inflammatory drugs, which are not ideal but better tolerated than steroids.
Again in the area of pain management, there is a critical unmet medical need around the management of severe pain, whether acute or chronic. Opioids (and morphine is the prototypical opioid) provide excellent pain management. Opioids used in pain management bind and activate the mu-opioid receptor. The mu-opioid receptor is a GPCR in the central nervous system. Binding of the mu-receptor reduces pain sensation, causes sedation, and even slows respiratory rate. mu-Opioid agonists are also highly additive. So, here is an example of on-target toxicity because the target is associated with toxic responses, such as addition. Note that reducing respiration rate is also a safety risk and can lead to patient death in cases of severe overdoses. Opioids are still used for severe pain management, but their shortcomings mean the drugs must be prescribed with care.