ED50

Issues of Concern

Research shows that even when manufacturers set dose estimation guidelines, it has an insignificant impact on what dose clinicians prescribe. Another overlooked aspect of the ED50 is the variation depending on a patient's weight, height, fat content, pharmacokinetics, and pharmacodynamics.[1]

ED50 for medications and the recommended dosages based on clinical studies are derived from surrogate endpoints (e.g., blood pressure after taking medication) rather than the drug's long-term effects on the body.[2]

Clinical studies have shown that mortality is often deemed too uncommon or too small of an endpoint to be particularly interesting for a medication. However, in a large patient population, medications with substantial clinical benefits may also lead to severe consequences and death. An example of this is digoxin, which has had efficacy in heart failure and atrial fibrillation but caused a net increase in mortality when administered in standard dosages.[1]

Optimal dosing balances efficacy and safety. Dosing in psychiatry is challenging due to subjective factors, and the dosage can vary significantly. The usual recommended daily dose of desvenlafaxine is 50 mg, but doses as high as 400 mg have been documented, exceeding the effective dosage (ED50). This practice increases the incidence of adverse drug reactions (ADRs) without clear therapeutic benefits. The absence of significant clinical advantage at increased doses of first-generation antipsychotics and the risk of severe adverse effects. It is important to note that higher doses may be necessary depending on the clinical scenario, but it is essential to comprehend ED50 for safe prescribing.[3]

Clinical Significance

When dosing drugs for significant periods, the dosage for the desired effect must be monitored to ensure that the patient does not approach the toxic dose.[4] Knowing the drug's ED50 is very useful in avoiding potential adverse outcomes.

A recent study found that prescription medications have contributed to over 10% of hospital admissions and over 15% of hospital mortality.[5] It is important to clarify that not all of these cases arise from using higher doses than necessary for the intended efficacy. Prescriptions with high dosages should be consistently reviewed periodically to ensure they do not lead to potentially toxic drug exposure levels. Research has found that prescribing medications such as aspirin and statins at dosages near their ED50 is the most effective from a preventative standpoint. For example, an 81 mg aspirin dosage after a first clinical heart event is just as effective as dosages of over 100 mg.[6] 

It is essential to consider the clinical endpoints for patients, as alterations in weight and age can affect the ED50 of medications. Based on established guidelines, clinicians often aim to meet specific metrics, such as HbA1c. However, failure to consider ED50 can result in patients receiving medication doses that exceed their toxicity threshold, which may be a standard dose for another patient.[1]

The therapeutic index (TI) should also be considered for better comprehension of ED50 (TI = TD50/ED50). LD50 is the lethal drug dose for 50% of the population, usually utilized in preclinical (animal) studies.[7] Medications with a lower therapeutic index (TI), like warfarin, lithium, and theophylline, require close monitoring due to their narrow margin of safety. On the contrary, medications with a very high TI (eg, penicillin) are generally safe. In one study, the ED50 for a motor block of intrathecally administered bupivacaine was reduced with advancing age.[8]

Nursing, Allied Health, and Interprofessional Team Interventions

The ED50 is a metric representing the dose of a medication that produces the intended pharmacological effect in 50% of the patient population studied during clinical trials. This value is derived from clinical studies and is used to help clinicians determine the optimal initial dose for their patients. An interprofessional team of physicians, pharmacists, nurses, and other healthcare professionals is necessary to monitor medication efficacy and safety according to patient factors, such as renal or hepatic function changes, disease state, and drug interactions, and ensure optimal patient outcomes.[9]

Nursing, Allied Health, and Interprofessional Team Monitoring

According to the FDA, medications demonstrating a narrow therapeutic ratio, where the ratio between the median lethal dose (LD50) and median effective dose (ED50) is less than 2-fold, or when there is less than a 2-fold difference in minimum toxic concentrations and minimum effective concentrations in the bloodstream, require careful titration and vigilant monitoring for safe and effective utilization.