Deciding Which Compound is the Best

It is my pleasure to introduce to you, a member of the MLC team, Chris Town, PhD.  Chris is a consultant in Drug Metabolism and Pharmacokintietics (PK).  He has spent over 30 years in the Pharmaceutical industry designing, executing and interpreting PK studies and conducting research in support of pre-clinical development, ultimately moving compounds from research projects into human studies.

Take it away Chris!!!

Somewhere in the course of any new drug project, you have to decide which compound(s) to take into development and eventually into man.  You hopefully have some compounds showing good activity in your in vitro assay.  Ideally, these compounds also show efficacy in your in vivo model.  You have to choose the compound from the active ones that is most likely to show efficacy in humans.  It must have characteristics that will allow you to get far enough in development that you can justify to your management and the FDA that you should do a first-in-human study.  Pharmacokinetics (PK) should play a role in choosing the compound that has the best chance of success.  No matter how good a compound’s in vitro activity is, it has to work in a human being, at a reasonable dose and dosing interval.  The pharmacokinetic studies that you run to choose the best lead will vary from project to project.  However, if you do the right studies and correctly interpret the data, you have a better chance of success in development.  Normally, you start in vivo testing with rodents.  They are small animals (less expensive) and don’t use a lot of drug in each study.  Rats and mice are the most commonly used rodents for in vivo pharmacokinetic and toxicity studies.  For example, you have to attain a reasonable multiple, of the expected efficacious human plasma concentration, in the rat.  You also need a concentration multiple in the second, non-rodent tox species, often the dog.

In order to accomplish this goal, I recommend that the first in-vivopharmacokinetic screen be done with the rat.  You might wonder why the rat? You can’t sell drugs to cure anything in a rat, so there’s no money to be made there!  However, rats are a very important species in drug development.  In addition to their use in toxicity studies, the pH in a rat’s stomach is closer to humans than the pH in a dog’s stomach.  So, rats can be used as a model for liquid formulation testing.  You can do a reasonable number of exploratory studies without using a lot of compound. When you test a compound in a dog for pharmacokinetics, formulation or any one of a number of other parameters, you use a lot of compound. Monkeys fall somewhere in between, but they are very expensive and difficult to maintain.  So, to gather the most information at a reasonable price and use the least amount of drug, rats are an excellent species.  I start with intravenous administration.  That way I get some idea of clearance and half-life which tells me a bit about the chances of getting high exposure in rat.  If you compare your in vivo data from the rat with in vitro data from microsomes or hepatocytes from rat, dog and human, you can determine whether the in vivo and in vitro clearances match in the rat and later in the dog.  If they do, you can predict that they might do the same in humans!  This will give you some confidence that this compound will have acceptable pharmacokinetics in man to be efficacious with QD (once a day) or BID (twice a day) dosing.

Human testing is where the REAL fun starts, I’ll let someone else talk about that!  😉


  • To be successfully developed, compounds must havegood pharmacokinetics in humans and the two species used for toxicology studies (commonly rats and non-human primates).
  • Compounds that don’t have optimal PK characteristics need to be eliminated early in the screening cascade while the best compounds move forward.
  • In order to save time and compound (and money!), the first in vivo PK screen should be an intravenous study using rats.