This app offers a visualization of how interspecies scaling adjustments and safety considerations influence the calculated HED
Instructions:
The ICH S9 guidance1 offers a structured approach to determining safe starting doses for first-in-human trials of systemically administered small molecule anticancer agents. It recommends scaling an appropriate "safe dose" established in animal toxicity studies to a human equivalent dose (HED) using relevant scaling factors. This HED is then further adjusted by a safety factor to arrive at a conservative starting dose for clinical trials.
Animal studies might not accurately predict immune system side effects in humans for immune-activating biologic drugs. These drugs can activate immune responses that animals don't experience in the same way. Because of this, the starting dose for these drugs is often based on the minimal expected level needed to see a biological effect Minimally Anticipated Biological Effect Level (MABEL) rather than animal toxicity.
When translating a safe dose observed in animals, like the highest non-toxic dose or the one with no-observed adverse effect level (NOAEL), to a HED, some adjustments need to be made. The US FDA recommends using a specific method called body surface area (BSA) normalization to account for the size difference between animals and humans2. This approach aims for a more accurate HED that reflects the different surface area available for the drug to interact with in each species. In this app we use the following formula: \[ \text{HED (mg)} = \text{human body weight (kg)} \times \left(\frac{\text{animal dose (mg)}}{\text{animal body weight (kg)}}\right) \times \left(\frac{\text{animal body weight (kg)}}{\text{human body weight (kg)}}\right) ^ {\left(1 - \text{scaling exponent}\right)} \]
The guidance also suggests that, for those biologic drugs given intravenously and with a large molecular weight (over 100,000 Daltons), scaling should be based on body weight instead of body surface area2. This means the HED in mg/kg would be the same as the dose in animals (mg/kg). In other words, the scaling exponent in this case would be 1, indicating a direct proportion between animal and human doses.
Compared to small molecules, biologics exhibit distinct pharmacokinetic properties. They often clear from the body through proteolytic degradation rather than processes like metabolism or renal excretion, which are more relevant for small molecules. Consequently, a scaling factor of 0.67, commonly used for small molecules, might underestimate the appropriate HED for biologics. The current litterature suggests a higher scaling factor of 0.8‑0.9 for biologics, supported by studies suggesting an exponent range of 0.79‑0.963.
Furthermore, the current litterature and guidances emphasize the importance of employing advanced PK/PD modeling when translating animal data to human doses3. This approach, along with MABEL estimation and therapeutic range considerations, leverages
Finally, a critical element in establishing the initial dose for a novel therapeutic is the incorporation of a safety factor. This factor compensates for inherent uncertainties in translating preclinical data to humans. These uncertainties encompass exaggerated pharmacological response, some limitations in animal toxicology, interspecies target variability, and PK uncertainties. The FDA suggests a default factor of 10 for initial clinical trials involving healthy volunteers2.