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Karin LiltorpKarin Liltorp, Ph.D., is currently working as principal scientist at Particle Analytical Aps., an analytical laboratory performing physical chemical characterization of pharmaceutical drugs.

In many of the larger pharmaceutical companies, the outcome of clinical studies is predicted using computer simulations. An example of such a program is SIMCYP—a program I have used with great enthusiasm, but other excellent programs likely exist. In some cases, the computer predictions are spot on, and in other cases they do not reflect the situation in real life at all. Then why use the simulations if you never know the reliability of the predictions? The primary reason is that whatever the outcome is, you obtain a much better understanding of your product.

In a computer simulation, the journey of an active molecule is followed from when it enters the stomach until it is excreted. The journey starts in the stomach where the drug dissolves and continues into the intestines where it is absorbed into the bloodstream. Following, it is exposed to various enzymes; it is metabolized; and finally it leaves the body. This is a journey described by a very large number (thousands!) of differential equations. At any time-point of the journey you can get information about the current situation (e.g., concentration in the intestine, plasma concentration, etc.).

The body is a complex system, and it is quite difficult to mimic real life: Humans vary a lot inside, e.g., the pH value of the stomach, the transit time in the intestines, the concentration of bile salts, enzyme abundance, etc. You cannot make experiments taking all these variations into account.

Computer simulations are based solely on the users’ input; input primarily originating from experimental data, i.e., there is no “computer-guessing.” The output is directly related to the input, and it is a really efficient way to use you experimental data optimally. Thus, the main advantage is that with the aid of computer simulations you can get really far using “fewer” good experiments..

In cases where you do not see agreement between the simulations and the clinic, you are actually able to learn quite a lot from the simulations: Are any of the input parameters incorrect? Are the interactions with certain enzymes over-predicted? Could it be the compound precipitates? Trying to fit the simulations to the real life data makes it possible to plan the following trials more optimally.

A unique strength of this program is that it forces people to talk across disciplines, because input from the whole development chain is required, and they learn to speak the same “language:” The analytical chemist has a simple way to explain the impact of a change in particle size in relation to plasma concentration. The ADME people can easily show the importance of enzyme X which should be taken into account. The formulation chemist can actually show the clinicians why it is not possible to solve all problems with a controlled release formulation and so on.

In my opinion, computer simulations are extremely relevant in order to understand the compound. Unfortunately most of these programs are still too expensive to use for smaller companies. Hopefully a more user-friendly (cheaper) version will see the market shortly.

Have you had good (or bad) experiences with any other computer simulation programs?