How Drugs Work: The Science of Pharmacokinetics and Pharmacodynamics.
Principles of Drug Action.
A drug undergoes three phases to achieve its intended purpose. These stages include the drug administration phase, pharmacokinetic phase, and pharmacodynamic phase. These phases form a conceptual framework that explains the drug’s course of action from administration, absorption, effects, and finally, its excretion from the body.
Approximately 80% of drugs are administered orally. The pharmaceutical phase is the initial stage where the drug is ingested. For absorption to occur, the drug must be converted into a solution form in the gastrointestinal (GI) tract. Therefore, drugs in solid form, such as tablets or capsules, must be broken down into tiny particles and dissolved into a solution through a process called dissolution (Dinis-Oliveira, 2023). Drugs ingested in liquid form are more easily absorbed since they are already in solution form.
Pharmacokinetics involves the processes of drug absorption, distribution, metabolism, and excretion. After dissolution, drug particles are absorbed through the surface of the small intestines. The GI tract is composed of lipid fats; thus, lipid-soluble drugs dissolve quickly as they pass through the tract. Drugs administered through other routes, such as ear drops and eye drops, are absorbed directly and do not pass through the GI tract or liver.
In the liver, drugs can be metabolized into various forms. Some medications are converted into more active forms, which are then distributed throughout the body via body fluids, often through the bloodstream (Holze et al.,2023). Others are metabolized into less active forms, which are then excreted from the body through urine or feces. Factors that may affect the absorption process include blood flow, pain, stress, depression, and pH levels. Some drugs are better absorbed in an alkaline environment, while others prefer an acidic environment.
Pharmacodynamics is the third and final phase in the drug action framework. It is concerned with the relationship between drug concentration and its effects on a patient. Drugs work by interacting with biological structures located inside cells, such as receptors and enzymes, to produce desired outcomes. Therefore, the concentration of a drug at these sites determines the duration and intensity of the effects at the site of action.
However, determining the intensity of a drug at the site of action is challenging. It requires a deeper understanding of the interaction between the drug and its target (Holze et al.,2023). Consequently, most drug-producing companies prefer manufacturing drugs that interact with specific receptors to minimize potential side effects.
What is Pharmacokinetics and pharmacodynamics?
Pharmacokinetics (PK) and pharmacodynamics (PD) are two closely related branches of pharmacology that study the movement of drugs through the body and their effects on the body, respectively. These concepts are essential for understanding how drugs work and for developing safe and effective drug therapies.
PK studies how the body handles drugs, including their absorption, distribution, metabolism, and elimination. Absorption refers to the movement of drugs from the site of administration into the bloodstream. Distribution refers to the movement of drugs from the bloodstream to the tissues and organs (Centanni, 2019). Metabolism refers to the chemical changes that the body makes to drugs, often making them less active. Elimination refers to the removal of drugs from the body, typically through the kidneys or liver.
PD studies how drugs interact with the body and how they produce their effects. This includes understanding the mechanisms of drug action, the receptors that drugs bind to, and the biochemical and physiological changes that drugs cause (Džidić-Krivić, et al.,2023).
The Interrelationship between Pharmacokinetics (PK) and pharmacodynamics (PD).
The two are intimately connected, working in tandem to dictate a drug’s overall impact. The drug’s PK properties, for instance, determine the quantity of the drug that reaches the target tissue (the site of action) (Holze et al., 2023). Meanwhile, the drug’s PD properties, such as its affinity for the target receptor, establish the extent of its effect.
The Significance of Pharmacokinetics (PK) and pharmacodynamics (PD) in Drug Development.
In comprehending how drugs function and in creating safe and effective drug therapies, pharmacodynamics (PD) and pharmacokinetics (PK) play a crucial role. Pharmacokinetics data can be employed to ascertain the ideal dosage of a drug, while pharmacodynamics data can be utilized to understand the mechanisms of drug action and to identify potential side effects.
Pharmacokinetics: Unveiling Drug Absorption, Distribution, Metabolism, and Excretion:
Absorption is the process through which drugs enter the bloodstream and reach their target sites. Factors such as drug formulation, route of administration, and physicochemical properties influence drug absorption. For instance, lipid-soluble drugs can easily cross cell membranes, while hydrophilic drugs may require specialized transport mechanisms (Holze et al., 2023). Additionally, the site of administration (e.g., oral, intravenous, or transdermal) affects the speed and extent of drug absorption.
Once absorbed, drugs are distributed throughout the body, facilitated by the bloodstream. Factors influencing drug distribution include tissue perfusion, protein binding, and drug solubility. Highly perfused organs, such as the liver and kidneys, receive a greater drug supply. Moreover, drug-protein binding can impact the distribution of drugs in the body, as only the unbound fraction of a drug can exert its therapeutic effects (Henneman et al., 2020).
Metabolism refers to the enzymatic conversion of drugs into metabolites, which are often more water-soluble and easier to eliminate. The liver, with its extensive enzymatic activity, plays a central role in drug metabolism. The cytochrome P450 enzyme system, comprising various isoforms, is particularly significant in drug metabolism (Yan et al.,2023). Genetic variations in these enzymes can lead to interindividual differences in drug metabolism and therapeutic responses
Excretion represents the elimination of drugs and their metabolites from the body. The kidneys are the primary excretory organs, eliminating drugs via urine (Džidić-Krivić, et al.,2023). Other routes of excretion include feces, breath, sweat, and breast milk. Renal function and glomerular filtration rate heavily influence drug excretion, and impairment in these processes can lead to drug accumulation and potential toxicity
Pharmacodynamics: Unraveling Drug-Receptor Interactions and Biological Effects:
Pharmacodynamics focuses on understanding how drugs interact with target receptors and produce their therapeutic effects. Key concepts within pharmacodynamics include drug potency, efficacy, and selectivity, as well as receptor theory and dose-response relationships.
2.1 Drug-Receptor Interactions:
Drugs exert their effects by binding to specific receptors in the body. When a drug binds to a receptor, it initiates a cascade of events that can lead to a desired therapeutic effect or biological response. The affinity and selectivity of a drug for its target receptor determine the strength and specificity of the drug-receptor interaction (Centanni, 2019). Affinity refers to the strength of the binding interaction, while selectivity refers to the ability of a drug to bind to a particular receptor over other receptors. The kinetics of drug-receptor binding, such as the rates of association and dissociation, influence the duration and intensity of drug action.
For example, a drug with high affinity and selectivity for a particular receptor will bind to that receptor more tightly than other drugs. This will result in a stronger and more specific drug-receptor interaction, which is likely to lead to a greater therapeutic effect (Roth, 2016). Additionally, a drug with a fast association rate will bind to its receptor more quickly, while a drug with a slow dissociation rate will take longer to dissociate from its receptor. These factors can all influence the duration and intensity of drug action.
The binding of drugs to receptors is a complex process that can have a significant impact on the therapeutic effects of drugs. By understanding the factors that influence drug-receptor binding, we can better understand how drugs work and how to optimize their use in the treatment of disease.
2.2 Dose-Response Relationships:
Dose-response relationships elucidate the relationship between drug dose and its corresponding therapeutic or toxic effects. These relationships are typically described by concentration-effect curves, such as the sigmoidal-shaped dose-response curve. Parameters derived from dose-response relationships, such as the maximum response (Emax) and the concentration required to produce 50% of the maximum response (EC50), provide important insights into the potency and efficacy of a drug (Hulme, 2018). Potency refers to the concentration or dose at which a drug produces its desired effect, while efficacy denotes the maximum effect achievable with a drug
2.3 Receptor Theory:
Receptor theory forms the foundation for understanding drug-receptor interactions. According to this theory, drugs interact with receptors through reversible binding, leading to the activation or inhibition of specific cellular processes. Various receptor types, such as agonists, antagonists, and allosteric modulators, have distinct effects on receptor activity and subsequent physiological responses (Rang et al., 2018). Agonists mimic the action of endogenous ligands, while antagonists block receptor activation. Allosteric modulators, on the other hand, regulate receptor activity indirectly.
The Dynamic Interplay of Pharmacokinetics and Pharmacodynamics:
Understanding the dynamic interplay between pharmacokinetics and pharmacodynamics is crucial for optimizing drug therapy and ensuring patient safety. Several key factors influence this interplay:
3.1 Time Course of Drug Action:
The time course of drug action is determined by the kinetics of both drug absorption and elimination, as well as the receptor binding and dissociation kinetics (Roberts et al., 2016). By analyzing the pharmacokinetic and pharmacodynamic properties of a drug, clinicians can develop dosing regimens that maintain therapeutic drug concentrations within the desired range for optimal efficacy
3.2 Therapeutic Window:
The therapeutic window represents the range of drug concentrations within which the desired therapeutic effect is achieved while minimizing adverse effects. Pharmacokinetic parameters such as the area under the concentration-time curve (AUC) and the minimum effective concentration (MEC) play a critical role in determining the therapeutic window (Gombar et al., 2021). Individual variations in pharmacokinetics, such as drug metabolism and clearance rates, may necessitate dose adjustments to maintain drug concentrations within the therapeutic window.
3.3 Drug-Drug Interactions:
Pharmacokinetic and pharmacodynamic interactions can affect the efficacy and safety of drugs. Pharmacokinetic interactions occur when one drug affects the absorption, distribution, metabolism, or excretion of another drug. Pharmacodynamic interactions occur when two drugs have additive, synergistic, or antagonistic effects on the same or different receptors (Yan et al.,2023). Clinicians must consider potential drug-drug interactions when prescribing multiple medications to ensure optimal therapeutic outcomes and avoid adverse reactions.
Factors Influencing Pharmacokinetic and Pharmacodynamic Processes in Patients.
Pharmacodynamics investigates the body’s response to drugs, while pharmacokinetics focuses on the body’s processing of drugs. Several factors can influence the pharmacokinetic and pharmacodynamic processes in a patient, including the following:
Physicochemical properties: The solubility of drugs in water is crucial for their absorption into the bloodstream. Additionally, lipid-soluble drugs are required to penetrate cell membranes and reach the systemic circulatory system. Absorption rates are dependent on the degree of lipid solubility, and modifying the chemical structure of a drug can enhance its absorption by increasing its solubility in fats.
Drug formulation: The formulation of a drug determines its dissolution or release from the dosage form. The degree of dissolution depends on the drug’s dissolution constant and the pH conditions at the absorption site. Different drugs may have varying dissolution levels, and the same drug can exhibit different dissolution degrees in different parts of the body due to variations in pH conditions.
Route of administration: Drugs can be administered through various routes, such as oral ingestion, injection (intravenously or IV), sublingual placement, inhalation into the lungs, cutaneous application, rectal or vaginal insertion, and transdermal application. Regardless of the route, a drug must be in a solution state to be absorbed into the circulatory system. Certain drugs are most effective when administered through specific routes (Ding & Zhang, 2020). For example, proteins and peptides are often administered through parenteral routes, such as IV, due to their large molecular sizes that hinder absorption through biological barriers.
Rate of excretion: Excretion involves the breakdown and elimination of drugs from the body, primarily facilitated by the kidneys. However, some excreted drugs can be reabsorbed into the bloodstream through the renal tubules, prolonging their effects. Tubular reabsorption can be affected by the pH of urine, and the alkaline or acidic nature of drugs can interfere with urine pH, impacting tubular reabsorption.
Clinical Applications and Future Directions:
The Intersection of Pharmacokinetics, Pharmacodynamics, and Personalized Medicine: Unleashing the Potential of Advanced Drug Delivery Systems
In the realm of clinical decision-making and drug development, the amalgamation of pharmacokinetics and pharmacodynamics holds paramount importance. Recent breakthroughs in pharmacokinetic modeling and simulation techniques, coupled with the burgeoning field of pharmacogenomics, have paved the way for personalized medicine approaches (Nair et al., 2023). By tailoring drug dosages based on an individual’s unique pharmacokinetic and pharmacodynamic profile, the potential for enhancing treatment efficacy while mitigating the risk of adverse effects becomes a tangible reality. Moreover, the advent of innovative drug delivery systems, such as nanoparticles and targeted drug delivery, presents an exciting frontier for optimizing drug bioavailability and fine-tuning pharmacodynamic responses (Ortega-Paz et al., 2023).
Personalized Medicine: Harnessing the Power of Individual Variability. In the realm of drug therapy, the concept of “one size fits all” is rapidly becoming outdated. The field of personalized medicine seeks to embrace the inherent variability among individuals by tailoring drug regimens to suit their unique characteristics (Tavakoli & Moghimi, 2022). By leveraging pharmacokinetic and pharmacodynamic data, clinicians can calibrate drug doses to achieve maximum therapeutic benefit while minimizing the likelihood of adverse reactions.
Pharmacokinetic Modeling and Simulation: Revolutionizing Drug Development. The utilization of pharmacokinetic modeling and simulation has revolutionized the landscape of drug development. These advanced computational techniques enable researchers to predict drug behavior within the body, thereby facilitating the optimization of dosing regimens. By integrating patient-specific data, including genetic information obtained through pharmacogenomics, researchers can construct sophisticated models that capture the intricacies of drug absorption, distribution, metabolism, and elimination (Ding & Zhang, 2020). Consequently, this knowledge empowers clinicians to make informed decisions, tailoring drug doses precisely to individual patients.
Pharmacogenomics: Unraveling Genetic Determinants of Drug Response. The advent of pharmacogenomics has shed light on the interplay between an individual’s genetic makeup and their response to drugs (Dinis-Oliveira, 2023). By elucidating the genetic variants that influence drug metabolism, transport, and target interactions, pharmacogenomics allows clinicians to identify patients who may exhibit atypical responses to specific medications. Armed with this knowledge, healthcare providers can design personalized treatment plans, accounting for variations in drug metabolism and optimizing therapeutic outcomes.
Novel Drug Delivery Systems: Pioneering Precision and Efficacy. In tandem with the progress made in pharmacokinetics and pharmacogenomics – a PhD dissertation topic example, the development of novel drug delivery systems has garnered significant attention. Nanoparticles, for instance, have emerged as promising carriers capable of encapsulating therapeutic agents with precision and efficiency (Ding & Zhang, 2020). By exploiting the unique physicochemical properties of nanoparticles, such as their tunable size, surface charge, and drug release kinetics, researchers can design drug delivery systems that enhance drug bioavailability and target specific tissues or cells. This targeted drug delivery approach minimizes off-target effects and maximizes therapeutic efficacy, revolutionizing the treatment landscape across various medical disciplines.
Embracing the Future of Precision Medicine.
The seamless integration of pharmacokinetics, pharmacodynamics, and personalized medicine holds immense promise for improving patient outcomes and redefining the landscape of drug therapy. As pharmacogenomics continues to unravel the genetic underpinnings of drug response, and pharmacokinetic modeling and simulation techniques advance further, clinicians can unlock the true potential of personalized medicine (Tavakoli & Moghimi, 2022). The development of novel drug delivery systems, exemplified by nanoparticles and targeted drug delivery, further augments precision medicine by optimizing drug bioavailability and enabling tailored pharmacodynamic responses. Embracing these advancements and their potential for patient-centered care ensures that healthcare professionals are at the forefront of the evolving landscape of clinical applications and future directions in medicine.
Pharmacokinetics and pharmacodynamics are inseparable components in understanding drug action and optimizing therapeutic outcomes. The knowledge of how drugs are absorbed, distributed, metabolized, and eliminated, coupled with an understanding of the mechanisms of drug-receptor interactions, provides a comprehensive understanding of drug behavior in the body. The integration of these concepts is vital for tailoring drug therapy, minimizing adverse effects, and achieving optimal therapeutic outcomes.
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Pharmacokinetics and Pharmacodynamics: What You Need to Know
Pharmacokinetics and pharmacodynamics are two important areas of pharmacology that help us understand how drugs work in the body. Pharmacokinetics is the study of how drugs are absorbed, distributed, metabolized, and excreted by the body. Pharmacodynamics is the study of how drugs produce their effects on the body. In this blog post, we will explain the basic concepts of pharmacokinetics and pharmacodynamics, and provide some examples of how they are applied in clinical practice.
Pharmacokinetics: What the Body Does to the Drug
Pharmacokinetics describes the movement of drugs in the body, from the time they are administered until they are eliminated. There are four main processes involved in pharmacokinetics: absorption, distribution, metabolism, and excretion.
– Absorption is the process of how a drug enters the bloodstream from its site of administration. The rate and extent of absorption depend on factors such as the route of administration (e.g., oral, intravenous, subcutaneous), the physicochemical properties of the drug (e.g., solubility, stability, size), and the physiological conditions of the patient (e.g., gastric pH, blood flow, food intake).
– Distribution is the process of how a drug spreads throughout the body fluids and tissues after entering the bloodstream. The degree of distribution depends on factors such as the plasma protein binding of the drug (e.g., albumin, globulins), the lipid solubility of the drug (e.g., lipophilic drugs can cross cell membranes more easily), and the tissue affinity of the drug (e.g., some drugs preferentially accumulate in certain organs or tissues).
– Metabolism is the process of how a drug is chemically transformed by enzymes in the body, mainly in the liver. The purpose of metabolism is to make drugs more water-soluble and easier to excrete. However, some drugs may become more active or toxic after metabolism. The rate and extent of metabolism depend on factors such as the genetic variation of enzymes (e.g., cytochrome P450), the induction or inhibition of enzymes by other drugs or substances (e.g., grapefruit juice, alcohol), and the age and health status of the patient (e.g., liver disease, pregnancy).
– Excretion is the process of how a drug is eliminated from the body, mainly in urine or feces. The rate and extent of excretion depend on factors such as the renal function of the patient (e.g., glomerular filtration rate, tubular secretion), the pH of urine (e.g., acidic or alkaline urine can affect drug reabsorption), and the presence of other drugs or substances that may compete for excretion (e.g., probenecid).
Pharmacodynamics: What the Drug Does to the Body
Pharmacodynamics describes the effects of drugs on the body, from the molecular level to the organ system level. There are three main concepts involved in pharmacodynamics: receptors, dose-response relationships, and drug interactions.
– Receptors are proteins that bind to specific molecules (called ligands) and trigger a response in cells. Drugs can act as ligands for receptors and modulate their activity. Depending on how they bind to receptors, drugs can be classified as agonists (activate receptors), antagonists (block receptors), or partial agonists (partially activate receptors).
– Dose-response relationships describe how the magnitude of a drug effect varies with different doses or concentrations of a drug. A typical dose-response curve has three phases: a low-dose phase where there is no or minimal effect, a middle-dose phase where there is a proportional increase in effect with increasing dose, and a high-dose phase where there is a plateau or decrease in effect with increasing dose. The dose that produces 50% of the maximum effect is called ED50 (effective dose 50%), and the dose that produces 50% of a toxic or lethal effect is called TD50 or LD50 (toxic or lethal dose 50%), respectively.
– Drug interactions describe how the effects of one drug may be altered by another drug or substance. Drug interactions can be classified as pharmacokinetic interactions (affecting absorption, distribution, metabolism, or excretion) or pharmacodynamic interactions (affecting receptors or dose-response relationships). Drug interactions can be beneficial (enhancing therapeutic effects or reducing adverse effects) or harmful (reducing therapeutic effects or increasing adverse effects).
Examples of Pharmacokinetics and Pharmacodynamics
To illustrate how pharmacokinetics and pharmacodynamics are applied in clinical practice, let us consider two examples:
– Paracetamol is a widely used analgesic and antipyretic drug that is rapidly and completely absorbed orally within 30-60 minutes; 25% bound to plasma proteins; widely and almost uniformly distributed in the body; extensively metabolized in the liver, primarily by glucuronide and sulfate conjugation into inactive metabolites which are excreted in urine . Paracetamol acts by inhibiting the synthesis of prostaglandins, which are mediators of inflammation and pain. The dose-response relationship of paracetamol is linear, meaning that the analgesic effect increases proportionally with increasing dose. However, at high doses (>4 g/day), paracetamol can cause hepatotoxicity due to the accumulation of a toxic metabolite (N-acetyl-p-benzoquinone imine) that depletes glutathione, a protective antioxidant in the liver . Therefore, the therapeutic window of paracetamol is narrow, and patients should be advised to avoid overdosing or combining paracetamol with other hepatotoxic drugs or substances (e.g., alcohol).
– Loperamide is an antidiarrheal drug that acts on μ (Mu)-opioid receptors in the myenteric plexus of the large intestine; decrease smooth muscle tone, and delay the passage of intestinal content . Loperamide has poor oral bioavailability (about 0.3%) due to extensive first-pass metabolism in the liver and low permeability across the blood-brain barrier . Therefore, loperamide has minimal systemic effects and does not cause central nervous system depression or addiction like other opioids. However, at high doses (>16 mg/day), loperamide can cause cardiac arrhythmias due to its inhibition of cardiac potassium channels . Therefore, patients should be advised to follow the recommended dosage and duration of loperamide therapy and avoid combining loperamide with other drugs that may prolong the QT interval (e.g., macrolide antibiotics, antipsychotics).
Pharmacokinetics and pharmacodynamics are essential concepts for understanding how drugs work in the body and how to optimize their therapeutic use. Pharmacokinetics describes how drugs are absorbed, distributed, metabolized, and excreted by the body. Pharmacodynamics describes how drugs produce their effects on the body. By applying pharmacokinetic and pharmacodynamic principles, clinicians can select appropriate drugs, doses, routes, and schedules for individual patients, and monitor their efficacy and safety.
: Introduction to Pharmacokinetics and Pharmacodynamics – ASHP. https://www.ashp.org/-/media/store%20files/p2418-sample-chapter-1.pdf
: Paracetamol poisoning – Wikipedia. https://en.wikipedia.org/wiki/Paracetamol_poisoning
: Difference between Pharmacokinetics and Pharmacodynamics – PharmaEducation. https://pharmaeducation.net/difference-between-pharmacokinetics-and-pharmacodynamics/
: Loperamide – Wikipedia. https://en.wikipedia.org/wiki/Loperamide
: Loperamide (Imodium): Drug Safety Communication – FDA Limits Packaging To Encourage Safe Use | FDA. https://www.fda.gov/drugs/drug-safety-and-availability/loperamide-imodium-drug-safety-communication-fda-limits-packaging-encourage-safe-use
Sample Assignment Question:
Discussion: Pharmacokinetics and Pharmacodynamics
As an advanced practice nurse assisting physicians in the diagnosis and treatment of disorders, it is important to not only understand the impact of disorders on the body, but also the impact of drug treatments on the body. The relationships between drugs and the body can be described by pharmacokinetics and pharmacodynamics.
Pharmacokinetics describes what the body does to the drug through absorption, distribution, metabolism, and excretion, whereas pharmacodynamics describes what the drug does to the body NURS 6521 week 1 Discussion: Pharmacokinetics and Pharmacodynamics.
When selecting drugs and determining dosages for patients, it is essential to consider individual patient factors that might impact the patient’s pharmacokinetic and pharmacodynamic processes. These patient factors include genetics, gender, ethnicity, age, behavior (i.e., diet, nutrition, smoking, alcohol, illicit drug abuse), and/or pathophysiological changes due to disease. When choosing medications and establishing appropriate dosages for patients, it is crucial to take into account specific individual elements that could influence the patient’s pharmacokinetic and pharmacodynamic responses. These factors encompass genetic makeup, gender, ethnic background, age, behaviors such as dietary habits, nutrition, smoking, alcohol consumption, and illicit drug use, as well as any pathophysiological alterations resulting from underlying medical conditions.
For this Discussion, you reflect on a case from your past clinical experiences and consider how a patient’s pharmacokinetic and pharmacodynamic processes may alter his or her response to a drug.
Review the Resources for this module and consider the principles of pharmacokinetics and pharmacodynamics.
Reflect on your experiences, observations, and/or clinical practices from the last 5 years and think about how pharmacokinetic and pharmacodynamic factors altered his or her anticipated response to a drug.
Consider factors that might have influenced the patient’s pharmacokinetic and pharmacodynamic processes, such as genetics (including pharmacogenetics), gender, ethnicity, age, behavior, and/or possible pathophysiological changes due to disease.
Think about a personalized plan of care based on these influencing factors and patient history in your case study.
By Day 3 of Week 1
Post a description of the patient case from your experiences, observations, and/or clinical practice from the last 5 years. Then, describe factors that might have influenced pharmacokinetic and pharmacodynamic processes of the patient you identified. Finally, explain details of the personalized plan of care that you would develop based on influencing factors and patient history in your case. Be specific and provide examples. NURS 6521 week 1 Discussion: Pharmacokinetics and Pharmacodynamics
Wooltorton, E. (2016). Direct-Acting Oral Anticoagulants: Less Frequent Monitoring, but Important to Know the Limitations. Canadian Medical Association Journal, 188(5), 379-380. doi:10.1503/cmaj.160016
Yan, T., Yu, L., Shangguan, D., Li, W., Liu, N., Chen, Y., Fu, Y., Tang, J. and Liao, D., 2023. Advances in pharmacokinetics and pharmacodynamics of PD-1/PD-L1 inhibitors. International Immunopharmacology, 115, p.109638.