calculating the maximum recommended starting dose for a drug

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The acronym MRSD stands for maximum recommended starting dose. Before starting clinical trials, a drug sponsor must determine the MRSD for a clinical compound. There are many ways to determine a compound’s MRSD. This video presents just one method that is commonly used. The method has three steps. One, determine the NOAEL – the no adverse effect level. Two, the NOAEL is converted to the HED – human equivalent dose. Three, a safety factor is applied to give the MRSD. The goal of the MRSD is to predict a clinical dose that will show no toxicity in healthy volunteers in a phase I trial.
The first step is determining the NOAEL – no observed adverse effect level. The NOAEL is determined through ascending dose studies in an appropriate preclinical species. The adverse effect observed in the ascending dose study should be relevant to toxicity that will be observed in patients. A weight loss drug may reduce appetite in animals. This would be an observed effect. Reduced appetite is consistent with the therapeutic effect, so reduced appetite would not be an adverse effect. Diarrhea or a change in heart rate, however, would be an adverse effect. Similar in sound to NOAEL is NOEL – no observed effect level. These are not the same and not interchangeable.
HED stands for human equivalent dose. NOAEL can be converted to HED through both factoring the mass difference between a preclinical species and human and an exponential factor that accounts for surface area differences between species and is a form of allometric scaling. A common equation for HED is shown. NOAEL has units of mg of drug per kg of animal mass. W is the weight of the animal or human (normally in kg). The exponential term is the allometric scaling term. Common values of b are 0.67 or 0.75. The units of HED are mg of drug per kg of human subject mass.
The typical safety factor used to determine MRSD from HED is 10. So HED is divided by 10 to give MRSD. Note that the units of HED are the same as the units of MRSD, typically mg of drug per kg of patient mass. Larger safety factors may be warranted if the compound is expected to be more active in humans than animal species. If the compound is expected to have higher bioavailability in humans, then the safety factor may also be increased.
Here is a quick sample calculation of MRSD. Let’s say we have a compound with a NOAEL of 3 mg/kg in monkeys – non-human primates, NHP. We need to determine the HED with our equation. The entire value of this exponential function can often be looked up in its entirety in tables according to the preclinical species and b-value. For NHP and a b-value of 0.75, the conversion factor is 0.47. That gives an HED of 1.4 mg/kg. Division by 10 for the safety factor gives an MRSD of 0.14 mg/kg.