Understanding how a body processes a therapy and a therapy’s effect on the body is a critical step for understanding safety and efficacy to support clinical trials. But the process of characterization differs between small-molecule therapies and biotherapeutics.
Associate Director of Early Scientific Engagement at Labcorp Drug Development, Robert Nelson, recently hosted a scientific session to discuss the basics of pharmacokinetics (PK), pharmacodynamics (PD) and immunogenicity assays and shared how these characterizations can help build a more complete picture of a drug and its effects.
PK is the study of what the body does to a drug by assessing the movement of a drug into, through and out of the body. Traditionally, PK evaluates absorption, distribution, metabolism and excretion:
- Absorption is how the target is administered into the body. For a small-molecule drug, this might be a tablet; for a biologic drug, it could be an infusion or subcutaneous injection
- Distribution studies where the drug goes in the body
- Metabolism looks at how the drug is broken down by the body
- Excretion examines how the drug leaves the body
PK evaluates how the level of a drug changes over time. This is typically performed by evaluating blood samples collected at various time points, before and at different times after administration of the drug. These samples are currently most often obtained with standard blood draws, but finger-prick sampling on a dried blood spot collection kit or through other patient-centric collection methods such as automated wearable devices are becoming more common.
To measure PK, a number of different analytical platforms can be used for small-molecule chemical drugs, such as liquid chromatography and mass spectrometry, while immunoassay is the go-to technique for measurement of PK for a biologic or protein therapeutic.
As today’s therapeutic modalities are growing in complexity, particularly in the cell and gene therapy field, techniques such as quantitative polymerase chain reaction serve an important role to determine where the gene therapy is going in the body and where it is expressed. For cell therapies, flow cytometry has proven extremely valuable to evaluate the persistent and expansion of the therapeutic cells within the body.
Regardless of the technique for measuring PK, the basic principles involve evaluating samples with a known concentration of the drug to construct a calibration curve.
In the figure above, the example shows the dose-response curve (blue line) in an immunoassay with known concentrations of drug from low to high. From this calibration curve, the concentration of drug in a sample obtained from a patient can be calculated by converting the response observed to the equivalent concentration (red arrows). As samples are collected at different time points, before and after the administration, the concentration of the drug versus time can be plotted.
The figure above shows a typical example for three dose levels—low, medium and high—for a small-molecule drug. The drug absorbs into the blood, is distributed through the body and then is eliminated. Understanding this information helps determine how often and how much of the drug is needed to maintain a safe and effective therapeutic level.
Evaluating a protein therapeutic, this graph compares two different administration routes: subcutaneous and intravenous. Here, the time scale is measured in days. Protein therapeutics typically have a much longer half-life, meaning they stay in the body much longer as they are eliminated from the body more slowly than small-molecule therapies. Dosing could take place every week, every two weeks or even every month because of the longevity of the treatments.
The role of PD
On its own, PK data only provide one piece of the puzzle. That’s where PD provides another dimension to evaluate what a drug does to the body. PD is the quantitative study of the relationship between the drug exposure, the PK, and the pharmacological or toxicologic responses. This involves assessing:
- Desired effects: For example, if studying an antihypertensive medication, PD data will determine if the treatment reduces blood pressure
- Undesirable effects: A medicine may have unwanted side effects; for example, evaluating PD data may determine if an insulin injection could cause hypoglycemia (low blood sugar)
- Duration of the action: PD studies how long the drug effect—desired or undesired—lasts and whether the effect is reversible
To measure PD, the assay types and analytical platforms used are very diverse given that what is measured depends on the drug’s mechanism of action, expected (desired) responses and potential adverse (undesirable) effects. Examples of PD assessments include:
- Target binding/engagement for a drug targeting a cytokine
- Alanine transaminase liver function test to determine liver toxicity of a drug
- Minimum residual disease assessment by flow cytometry to determine if a treatment eliminates leukemic cancer cells while retaining the healthy cells
- MRI to determine if an oncology treatment reduces tumor volume
While assays can differ in the PD space, it’s important to choose endpoints that evaluate both the benefits of the drug treatment and the risk of adverse events.
Evaluating the PK/PD relationship
Uniting the PK and PD datasets creates the PK/PD relationship. This is important because PK data can then be correlated with the efficacy data to determine the minimum effective concentration of a therapy.
On the right side of the figure above, a treatment is administered every three weeks at different dosing regimens. The PK data are then correlated with efficacy data to determine the minimum effective concentration, along with the toxicity data to evaluate the minimum toxic concentration. This process identifies the therapeutic window every two or three weeks; however, this may vary among different individuals, which is why it is essential to study PK and PD in the controlled environment of clinical trials to ensure that drugs are prescribed and administered to patients in a safe and effective manner.
In some treatments, there may be a very narrow therapeutic window. Here, the drug must be monitored very closely to have the beneficial effects while avoiding the undesirable side effects. If a very wide therapeutic window is observed, it may be safe to administer a larger dose of the drug without side effects and still observe beneficial therapeutic effects. By evaluating these PK/PD relationships, drug developers can better understand the benefits and risks of a drug.
Immunogenicity for biologic drugs
Immunogenicity is a substance’s ability to provoke an immune response in the body. Regarding biotherapeutic drugs, which are large-molecule biologics, the immune system can recognize them as a foreign. In some cases, like vaccine development, immunogenicity is a desired response to build up a defense of antibodies and cells.
However, with biotherapeutic drugs, unwanted immunogenicity can be an obstacle to drug development. Therefore, it is necessary to evaluate humoral immunogenicity (antibody response) and, in some cases, cellular immunogenicity because an immune response has the potential to affect the PK, PD, safety and efficacy of a treatment.
The figures above show an example of the consequences of immunogenicity. On the left side, the PK profiles of two subjects are shown as the drug is dosed and cleared over time. In the second subject (PK2), the drug starts to clear very rapidly after the third and fourth doses, meaning that exposure cannot be maintained in the subject.
On their own, the PK data on the left can’t elucidate what is happening to the PK2 subject. But if anti-drug antibody assay data are integrated (shown as “ADA” in the figure on the right), an immune response to the drug in the PK2 subject is observed. Here, the anti-drug antibodies are increasing rapidly, which is the most probable cause of the observed rapid clearance of the drug.
Building a bigger picture
Assessing the PK, PD and immunogenicity allows drug development sponsors and their CRO partners to build a bigger picture and deliver insights for more informed decision-making. In addition, by understanding their drug’s action, beneficial effects and adverse effects, sponsors can better navigate the clinical trial space.