By Rachel Rozakis, PharmD, Clinical Pharmacologist II and Ben Kennard, MS, CPMS Intern
Pharmacodynamics (PD) is the study of how drugs affect the human body given their mechanism of action. In contrast, pharmacokinetics (PK) is the study of what the body does to the drug and describes information about ADME: absorption, distribution, metabolism, and excretion.
PK and PD data comprises approximately 25% of the information contained in a drug’s package insert/label, which includes a drug’s exposure (i.e., PK parameters [Cmax and AUC]) and response (i.e., efficacy and safety). Specifically, PK/PD describes the relationship between drug concentration (PK) and the resulting physiologic effect (PD). PK/PD also informs the time-course of PD effects as related to the PK profile.
Clinical PD studies evaluate a drug’s effects on the body by measuring certain “endpoints” or “biomarkers,” which differ from drug to drug and by mechanism of action. For example, receptor binding (such as the binding of an oncology drug to specific receptors on a tumor) or the production of a chemical reaction (such as an antacid’s production of neutral salts in the gastrointestinal tract) are both unique mechanisms that result in different PD endpoints.
Understanding PD endpoints allows drug developers to characterize the onset, degree, and duration of a drug’s effect on the body, which cannot be fully described by PK parameters. Therefore, PD studies and subsequent PK/PD analyses play an important role in ensuring the development of safe and effective therapies, at an optimal dose, for patients in need.
Principles of Pharmacodynamics
PD endpoints may include pharmacological measures (e.g., change in blood pressure) or biomarkers (e.g., protein changes when a target is engaged). The dose-exposure-response (PK/PD or E-R) relationship helps to inform the optimal dose that should be taken in order to achieve the desired drug exposure and physiologic response. A dose must be selected that will allow the drug to maintain a certain level of exposure (in order to either bind to specific receptors in the body or otherwise exert its mechanism of action), while also not causing excessive toxicity.
Additionally, desired plasma concentrations of a drug usually lie within a certain therapeutic window, which is defined by a maximum safe and a minimum effective concentration. Supratherapeutic concentrations above the therapeutic window can lead to adverse effects, while subtherapeutic concentrations can lead to poor efficacy. Understanding a drug’s pharmacodynamics allows drug developers to find the ideal therapeutic window.
PD studies may be conducted in vivo (within living organisms), in vitro (outside of living organisms in a controlled environment) and in silico (via computer simulations). Preclinical in vitro studies often use cells, while preclinical in vivo studies utilize animal models. Multiple animal models are usually studied before clinical in vivo human studies are initiated, primarily in order to characterize safety. In vivo, in vitro, and in silico PD studies help optimize dose selection, provide important information on safety, and inform a program’s clinical study designs.
With in silico studies, a drug’s structure can be modeled/simulated against known targets to predict effects that may occur in the body (such as adverse drug reactions) without conducting additional clinical studies. In silico PD studies can be advantageous because they are cost-effective and produce results quickly, however in silico models still require some nonclinical and/or clinical data to validate the model.
Why are Pharmacodynamic Studies Important?
PD studies can occur early (in Phase 1 and 2) or later (in Phase 3 or post marketing) and play an important role in demonstrating the safety and efficacy of a drug. Assessment of PD endpoints and biomarkers can provide an early read of the potential for efficacy and help to inform drug development decisions prior to conducting large pivotal clinical trials.
These studies help determine the dose or dose range of a drug that is needed to achieve a meaningful response without causing severe adverse effects. Inadequate characterization of a drug’s PD can lead to improper drug dosage, which can subsequently lead to many negative effects including:
- Acute CNS Abnormalities (e.g., confusion, coma, seizures)
- Acute CV Conditions (e.g., prolonged QT, vital sign changes)
- Cell Mutations & Cancer
- Chronic Conditions (e.g., neuropathy, pulmonary fibrosis, metabolic syndrome)
- Death
- End-Organ Damage (e.g., kidney, liver)
What Affects a Drug’s Pharmacodynamic Response?
The complexity and variability of human physiology, as well as multiple external factors (environment, diet, concomitant medications, etc.), can impact the safety and efficacy of a drug. Additionally, a dose of drug which is optimal for one patient may be ineffective or even toxic in a different patient. Therefore, clinical studies must consider intrinsic and extrinsic factors to determine the proper dose (or dose range) for different types of patients and for different patient populations. Known factors influencing PD as well as PK include:
- Age
- Sex
- Body weight or body surface area
- Pregnancy
- Kidney and liver function
- Drug interactions
- Smoking
Organ Function
One of the key factors that affects PD response is organ function, particularly that of the liver and kidney. Because these organs are involved in the clearance of many drugs, impaired function of either the liver or kidney can significantly impact a drug’s efficacy and safety. For example, a patient with impaired kidney function may eliminate a drug more slowly through the urine, leading to higher exposure of the drug and thus increased risk of toxicity.
Age
Age is also an important factor which influences PD. Younger individuals such as neonates are vastly different from adults in terms of physiology and often cannot be given drugs or doses meant for older children or adults. Elderly individuals also have different physiology from younger adults, which impacts PD. Advanced age is also accompanied by increased risk of drug interactions (through polypharmacy), organ dysfunction, and chronic disease which are all factors that must be considered.
Diseases and Disorders
Diseases or disorders can alter normal physiology and thus PD response. For example, a disease/disorder can change receptor sensitivity, receptor shape, or protein structures. If the disease/disorder alters a drug’s concentration at the site of action, it may impact the exposure-response relationship and therefore efficacy or safety. Some diseases/disorders that can affect PD include:
- Genetic Mutations
- Hyperthyroidism
- Insulin-Resistant Diabetes Mellitus
- Malnutrition
- Myasthenia Gravis
- Parkinson’s Disease
Conclusions
Pharmacodynamics is an important piece of the drug development puzzle when it comes to understanding exposure-response (PK/PD) relationships, optimal dose and dose regimens, and confirming safety and efficacy, which are all critical for successful regulatory approval. Assessing factors that can impact the PD of a drug such as organ function, age, and disease is also an important step in the process. Using the information gathered from PD studies, dosage adjustments for patients in specific populations may be provided in the drug label.
Allucent has a specialized focus in PK, PD, clinical pharmacology, and model-informed drug development (MIDD). We translate complex PK and PD data into actionable insights across the entire drug development spectrum. Contact our team of talented individuals to learn more about the variety of PK/PD analyses and services we provide and how they can benefit your drug development program.