Pharmacokinetics, toxicokinetics and safety margins
A selection of talks on Pharmaceutical Sciences
Hello, my name is Mark Rogge, I'm the Senior Director for Drug Metabolism and Pharmacokinetics at Biogen Idec Corporation. I've been in industry for about 25 years, most of my experience is in the pre-clinical and clinical development areas. The topic of my lecture is: Pharmacokinetics, Toxicokinetics and Safety Margins.
We'll start this lecture with considerations around first-in-human (FIH) dosing and clinical progression, discuss expectations for both the project team and senior management, talk about terms, definitions and concepts that are important around this topic, follow up with a safety margin example and finish with some concluding comments.
Let's start our discussion with first-in-human (FIH) dosing and clinical progression considerations. Safety is the most important, in fact, the paramount consideration as we enter into and progress through human trials. The FIH dose is often the most risky dose in the clinical development program, since until we have some human data, we do not understand the pre-clinical safety database as representative and valid, in terms of understanding safety issues that may arise during the clinical program. Dose escalation is also an important consideration. We must maintain appropriate safety margins as we progress through, and approach what we believe is going to be the maximum dose administered in the clinical program. Multiple dose exposure or repeated administrations in a single patient become very important, since often in the pre-clinical setting the regimens are different from those that will be administered in the human program. Consequently, we need to understand the nature of the exposure-toxicity-response relationship. Do peak concentrations cause the toxicity to occur? Is it maintenance of a concentration above a threshold that causes the toxicity? When we begin to understand that relationship, we can better relate the pre-clinical safety database to that database that's being developed in the human setting. Often, clinical programs start in healthy subjects and then progress into the patient population. More and more clinical development is being initiated in the patient population. Depending on the disease and the patient population intended to be treated, it is not uncommon for these patients to be debilitated, and therefore a higher safety margin or lower doses may be warranted as we initiate that human program. Special populations are often overlooked. Special populations encompass children, the elderly, patients with renal disease or hepatic disease. Like patients, they may be more susceptible to toxicities and higher safety margins or lower doses may be warranted. Let's talk for a minute about dose selection. Any therapeutic is going to be safe if the dose is low enough, it's also going to be toxic if the dose is high enough. It is imperative that the doses we choose in our human trials are both intelligent and informative. Doses must never be so high that they produce unnecessary risk of toxicity in the healthy subject or patient. At the same time, they must not be so low or infrequently administered that they do not add value to the clinical database and allow the program to continue forward.