For anyone who follows drug development closely, the terms pharmacodynamics (PD) and pharmacokinetics (PK) will likely be familiar. These terms are often used in preclinical drug research and in early phase clinical trials . In the simplest terms, pharmacokinetics refers to how a drug moves throughout the body, while pharmacodynamics is how that drug affects the parts of the body that it reaches.

All drugs act on what is known as a “target” – a specific disease-related process in the body that they modify. Understanding the PK and PD profiles of experimental drugs are essential steps in determining whether a drug can effectively reach this target in the body and then have the intended effect upon it. Over the course of a drug’s development, it will undergo PK and PD studies – in animals first and, eventually, in humans.

The First Step: Tolerability or Safety Studies

When testing a new drug either in an animal model, or in the first phase of clinical trials, researchers will often begin with a tolerability or a safety study. These studies, as the name implies, determine how much of a drug can be taken before having adverse effects. Once they have this information, they can begin to conduct a PK study to learn how the drug moves throughout the body, and to find the optimal dose and the best route of administration.

Pharmacokinetic Studies

“A PK study looks at how a drug moves into, through, and out of the body,” says Dr. Theo Hatzipetros, Ph.D., the ALS Therapy Development Institute’s (ALS TDI) Director of Pharmacology. “Drug levels over time vary depending on the way a drug is absorbed, distributed, how it’s metabolized, and how it’s excreted.”

In a typical PK study, researchers will collect blood, and other tissue samples or perform imaging techniques, over a period of time, to determine where the active ingredients of the drug, or other substances created as the body breaks down called metabolites, end up at any given moment. Sampling usually continues until there is no more trace of the drug. Using these data, researchers can get a clearer picture of the factors contributing to the levels of drug over time.

“By studying the way the drug concentrations vary in the different tissues over time,” says Dr. Hatzipetros, “we can adjust the frequency and methods of administration. Based on the way the PK profile looks, you might choose to dose the drug more or less frequently, give higher or lower doses, or you might choose to give it through a different route of administration. If you gave it orally initially, and you don't have enough drug in the tissue of interest, you might give it via an intraperitoneal injection instead that bypasses the gastrointestinal tract.”

When developing drugs for ALS, for example, researchers often want their drugs to reach the cells primarily affected by the disease, such as the upper and lower motor neurons in the central nervous system. Therefore, it is important for researchers to determine the PK profile of drugs in the brain and the spinal cord in order to ascertain whether the drug is able to cross the blood-brain barrier.

Pharmacodynamic studies

When researchers know that their drug is getting where it needs to go in the body, the next step is to understand how it is affecting the body. This is accomplished through a PD study. In order to make sure the drug is having the desired effect, researchers need to find and measure “pharmacodynamic markers” – or biological characteristics that they believe will change in response to the drug.

Pharmacodynamic markers are usually very specific to the mechanism of action of the drug,” says Dr. Hatzipetros. “For example, if you expect your drug to correct the misfolding of SOD1 protein, thereby decreasing the aberrant form of SOD1, then a good pharmacodynamic marker would be misfolded SOD1 levels. If your drug was meant to upregulate or downregulate the expression of a gene, like SOD1, you would look at levels of proteins transcribed by that gene.”

Many drugs are developed with a specific target in mind, and PD studies are essential for making sure they are having the desired effect on this target. At other times, researchers may not fully understand a drug's mechanism of action even though it has shown promise in cellular models of ALS. In these cases, surrogate PD markers can be helpful for forming an informed hypothesis of what target the drug could be affecting to produce these results.

PK and PD studies in preclinical research and clinical trials

PK and PD studies are essential in both preclinical research in animals and in human clinical trials. It is important to understand the PK and PD characteristics of a drug before conducting larger “efficacy” studies that are designed to determine whether the drug is efficacious in treating the disease. These efficacy studies can take several months because the animals being tested must be allowed to go through the entire course of their disease. By eliminating drugs that do not have good PK and PD characteristics before testing them for efficacy, researchers save valuable time and resources. The results from all these studies are important both for identifying promising candidates and informing the design of later trials in humans.

A lot of what we find during preclinical research informs the clinical design in humans,” says Dr. Hatzipetros. “You will of course have to do safety and dosing studies in humans as well, but what you discover in a mouse model can give you a good idea of what to expect about safety, pharmacokinetics, and pharmacodynamics. It doesn't translate fully, but it may also be useful information for predicting efficacy.”

If a drug makes it through preclinical testing, it will also need to go through similar studies in humans. Generally, a Phase 1 study looks at safety and dose determination. These are usually small studies, and often recruit healthy volunteers rather than people with the disease in question. Like in preclinical PK studies, they look to find the maximum safe dosage, track potential harmful side effects, and make sure the drug is showing up in the parts of the body where it is expected to be.

Phase 2 studies similarly correspond to preclinical PD studies, in addition to investigating a treatment's optimal dosing levels and beginning to gather efficacy data. However, the methods available to track a drug’s PD characteristics in humans are more limited than in animal studies. In preclinical studies, researchers can examine the effects of drug in a variety of animal tissue which obviously could not be taken from a living human being. Instead, they must rely on biomarkers, biological characteristics that can be measured, often in the blood, to determine the presence of a disease and/or its progression. There are currently no biomarkers for ALS that are able to reliably measure a drug’s efficacy – presenting a challenge for researchers in generating PD data. To address this, finding biomarkers for ALS is one of the most important research goals at ALS TDI, and one of the primary goals of our Precision Medicine Program (PMP).

Dr. Hatzipetros emphasizes that good preclinical PK and PD data are essential for designing efficient and effective clinical trials later on. That’s why at ALS TDI, we have developed the world’s leading preclinical research program in animal models of ALS. By deeply understanding how potential drugs affect animal models of the disease, we’re able to better identify drugs that could show promise for treating ALS – and eliminate treatments that are more likely to fail.

The better the design and execution of these early studies, the higher the success rate of the later studies,” Dr. Hatzipetros says. “This saves money, it saves time, and it saves both human lives and animal lives. But, even if the outcome of the early stages is not a good one, it's still overall better, because, you know not to proceed with an efficacy study. As they say in pharma, it's better to fail early than fail late. If by doing your tolerability and your pharmacokinetic studies, you discover that this is not a good drug, and then you abort the future studies, it's better than not getting that crystal clear answer and then failing later.”

What to do next: