Chapter 16-1. Pharmacology(PK/PD)
Recommended Reading : 【Chemistry】 Lecture 16. Reaction Kinetics, 【Biology】 Lecture 37. Biology Experiments
1. Overview
2. Pharmacodynamics
3. Pharmacokinetics
4. Clinical Trials
b. Drug Library
1. Overview
⑴ Pharmacology : Biochemistry that studies drugs and the body’s response to their administration.
⑵ Differences between Pharmacodynamics and Pharmacokinetics
① Pharmacodynamics : Related to receptors, ion channels, enzymes, immune system, etc.
② Pharmacokinetics : Related to absorption, distribution, metabolism, and excretion.
○ The four aspects above are collectively referred to as ADME.
2. Pharmacodynamics (PD)
⑴ Overview
① Definition : Related to receptors, ion channels, enzymes, immune system, etc.
② Tests on pharmacodynamics are mainly conducted in Phase 1 clinical trials to observe enzyme inhibitors or drug activity.
⑵ Constant 1. Ki (inhibition constant)
⑶ Constant 2. Kd (dissociation constant)
① Definition : The equilibrium constant for dissociation reactions; the larger the Kd, the more dissociation occurs.
② Kd is more commonly used than Ki because it can be easily determined through graphs.
③ Relationship formula
④ Graph interpretation : When [R·L] / [R]T is 0.5, the ligand concentration [L] corresponds to Kd.
Figure 1. Interpretation of the graph for Kd.
⑷ Constant 3. Bmax
① Total concentration of receptors.
② Unit : ligand bound / mg protein.
⑸ Constant 4. IC50
① IC50 : The inhibitor concentration at which 50% of the original ligand can dissociate.
○ Competitive binding : Treating receptors with a fixed concentration of hot ligand first, followed by varying concentrations of cold ligand to observe hot ligand dissociation.
② Dose-response curve (DRC).
Figure 2. Dose-response curve and IC50.
③ Cheng-Prusoff Equation : Given fixed ligand concentration [L] and Michaelis constant Km.
⑹ Constant 5. LC50
① Dose-response curve.
Figure 3. Dose-response curve and LC50.
3. Pharmacokinetics (PK)
⑴ Definition : Related to absorption, distribution, metabolism, and excretion.
① These four aspects are collectively referred to as ADME.
② PK parameters:
○ Bioavailability F (%) = Systemic circulation dose (mg) / Administered dose (mg) × 100.
○ Absorption rate constant ka (/hr) = Systemic circulation rate (mg/hr) / Residual amount at absorption site (mg).
○ Volume of distribution Vd (L) = Amount in body (mg) / Plasma concentration (mg/L).
○ Clearance CL (L/hr) = Elimination rate (mg/hr) / Plasma concentration (mg/L).
⑵ Model 1. Monoexponential Model
① Graph : Corresponds to the first-order reaction in reaction kinetics.
Figure 4. Monoexponential Model.
○ AUC (area under the curve).
○ Elimination rate k is defined as follows.
○ Doubling the initial dose : Half-life remains constant, and the time in the body increases only by one half-life.
② Steady state through chronic dosing.
○ It takes approximately five half-lives to reach steady state.
Figure 5. Steady state through chronic dosing.
○ Loading dose : Increasing the initial dose to reach steady state faster. Important for long half-life cases.
Figure 6. Concept of loading dose.
⑶ Model 2. Multicompartment Model
① Graph.
Figure 7. Graph of the multicompartment model.
② Explanation of each phase:
○ Phase 1. Absorption phase.
○ Oxidation, reduction occur to activate the drug upon initial intake.
○ Sulfation, glucuronidation, acetylation occur to inactivate the drug for excretion.
○ Phase 2. Postabsorption phase (distribution phase).
○ Phase 3. Elimination phase.
○ Cmax, tmax (time at Cmax).
Figure 8. Three phases of the multicompartment model.
③ ABC (accelerated blood clearance).
○ Definition : A phenomenon where drugs are rapidly excreted initially, followed by slower excretion.
○ IgM antibody is known to be involved in the ABC phenomenon of nanodrugs.
⑷ Pharmacokinetic experiments.
① If not completely excreted through urine, it can be interpreted as accumulating in the body.
② If not largely converted into metabolites, it can be interpreted as low bioavailability.
③ If AUCs of oral and IV administration are nearly identical, it can be interpreted as high absorption and hydrophilicity.
④ In oncology research, a tumor-to-liver ratio of 0.5 or higher indicates good pharmacokinetic properties.
⑴ Overview.
① Drug development stages:
○ Drug discovery : 3–5 years.
○ Preclinical : 1–2 years.
○ Clinical trials : 6–7 years.
○ FDA approval : 1–2 years.
② About 50–60 new drugs are approved by the FDA each year.
③ Costs are increasing, and failure rates are as high as 90%.
④ Most failures are due to lack of therapeutic effects.
○ Efforts are being made in Phase 1 to find efficacy and dose.
○ Phase 0 studies are introduced to test on humans earlier.
○ PET imaging is a possible strategy.
⑵ Phase 1 Clinical Trial : Exploratory clinical trial.
① Involving about 20–80 people.
② Type 1. Conducted on healthy volunteers for safety assessment.
③ Type 2. Anti-cancer drugs : Tested on a few volunteers with terminal cancer, etc.
④ Objectives:
○ Pharmacokinetics (PK) : Theories on ADME.
○ Interaction.
○ Safety (dose-dependent).
○ MTD (maximum tolerated dose), tolerable dose range, dose-tolerance study.
○ PK / PD study.
⑤ Methods:
○ Dose-response curve : NOAEL, NOEL, MED (minimum effective dose), MABEL.
○ Single dose rising, multiple dose rising.
○ Drug-drug interaction.
⑶ Phase 2 Clinical Trial : Tested on more people; exploratory clinical trial.
① Involving about 100–200 people.
② Early Phase 2 (IIa) : Efficacy testing.
③ Late Phase 2 (IIb) : Dose finding.
⑷ Phase 3 Clinical Trial : Final stage of clinical trials for market approval; confirmatory trial.
① Conducted on a large scale for statistical confirmation.
② Objectives : Confirmation of safety and therapeutic effect.
③ Typically takes 5–6 years to obtain market approval (long-term).
⑸ Phase 4 Clinical Trial : Long-term evaluation of efficacy and safety after new drug marketing.
① Post-marketing surveillance.
Input: 2022.04.22 12:07