Man or Mouse? The Difficulty in Calculating Drug Doses
I’m working with a pharmaceutical company preparing for their first in-human trial. One problem that presented itself was conversion of doses used in animal pre-clinical testing to appropriate levels for humans. In theory this seemed fairly straightforward, in practice it was anything but.
In theory: theory and practice are the same.
In practice: they’re not!
First in human pharmaceutical studies require extrapolation of dosing from animal laboratory experiments, a critical task that is far from straightforward. Interspecies allometric scaling for dose conversion from animal to human studies is one of the most controversial areas in clinical pharmacology. Allometric approach considers the differences in body surface area, which is associated with animal weight while extrapolating the doses of therapeutic agents among the species.
It should be emphasized that the common perception of scaling of dose based on the body weight (mg/kg) alone is not the right approach. This is primarily because the biochemical, functional systems in species vary which in turn alter pharmacokinetics. Therefore, extrapolation of dose from animals to humans needs consideration of body surface area, pharmacokinetics, and physiological time to increase clinical trial safety.
In a nutshell, the human equivalent dose (HED) is calculated using a calculation based on standard body surface area (man v mouse or other trial species) from the no observed adverse effect levels (NOAEL), established via pre-clinical animal toxicology studies. The HED is then divided by 10 to increase the factor of safety to yield the first human dose level, and scaled up for human body weight (70kg).
So, it’s complicated but basically maths? I’m afraid not! There are some more factors to be considered and this is where the assistance of a pharmacokinetic (PK) expert is invaluable. Here are just some of the things that PK expert needs to consider:
Larger animals have lower metabolic rates
Physiological process of larger animals is slower
Larger animals required smaller drug dose on weight basis
Pre-clinical doses are usually injected as opposed to tablet ingestion
Drugs in the bloodstream have to cross the blood-brain barrier (BBB), the speed of this will be dependent on molecule size and the drug’s chemical properties
Moral of the story? Be prepared to recognise when theory and practice are likely to diverge and don't be afraid to use of expert advice strategically.