MBSS1 Basics of Phamacokinetics 2021-22 Slides - Tagged.pdf

Basics of Pharmacokinetics MBSS-PPS Dr Richard Amison Dept. of Pharmacology & Therapeutics  Learning Outcomes  Discuss First Principles of PK  The importance of numbers  Zero order and First order Kinetics  One a...

Basics of Pharmacokinetics MBSS-PPS Dr Richard Amison Dept. of Pharmacology & Therapeutics  Learning Outcomes  Discuss First Principles of PK  The importance of numbers  Zero order and First order Kinetics  One and two-compartment models  Elimination rate constant (k) and half-life  ADME  Absorption  Distribution  Metabolism  Excretion  Bioavailability  Pharmacodynamics and the relationship between PK and PD  Pharmacokinetics: First Principles Some definitions Pharmacokinetics (PK): What the Body does to the Drug Pharmacodynamics (PD): What the Drug does to the Body PK/PD: The relationship between the two Drug Properties: The importance of numbers Drug Dose Clearance (Cl) Volume of Distribution (Vd) Half-life (t1/2) Bioavailability (mg) (L/h) (L) (hours) (F) (%) Aspirin 300 39 11 0.3 68 Propanolol 80 50 270 3.9 36 Diazepam 2 2 77 55 100  Rates of Reaction Zero Order Kinetics First Order Kinetics Rates of Reaction continued Most drugs follow first order kinetics = No Accumulation Zero order Kinetics e.g. Phenytoin = Accumulation Zero Order Kinetics can result in overdose  Compartment Models One Compartment Model Two Compartment Model Compartment Models continued Single Compartment models  Instantaneous Distribution  Monophase decline in plasma [drug] Two Compartment Model  Distribution between multiple compartments  Equilibrium between K1-2 and K2-1  Biphasic decline Multi-compartment models can exist Calculating Half-life (t1/2) Half life (t1/2): This is the time taken for the plasma concentration of a drug to decline by 50% On a monoexponential decline curve, the half-life can be estimated anywhere on the curve Concentration of Drug A at to [A]0: 20,000ng/ml [A] Declines by 50% to 10,000ng/ml in 20 minutes [A] Declines from 4000ng/ml to 2000ng/ml in 20 minutes Half-Life for Drug A = 20 minutes How do we calculate the elimination rate constant (k)?  Calculating the elimination rate constant (k) When considering an IV bolus of Drug A When involving first order kinetics, then: And at any time (t) 𝐴= 𝐴 0 ∗ exp ⁡(− 𝑘∗ 𝑡) Where: To visualise more simply A = Amount of drug A A0 = Amount of drug A at Time 0 Linearise the curve by converting plasma drug concentration to K= Elimination Rate Constant the natural logarithm and plot against time t = Time K = Slope A0 = Intercept on x axis  Calculating the elimination rate constant (k): Linearisation Linearise the curve by converting plasma drug concentration to the natural logarithm Slope of the line = Elimination rate constant (k) You can calculate this using 2 techniques 1) Linear Regression analysis 𝑦 =𝑚𝑥 +𝑐 2) Estimate Gradient using Concentration and time For Drug A: k = -0.035 At t0 (y intercept) ln [A] = 9.9 (20,000ng/ml) t1/2 = Ln(2) /  Relating t1/2 and k Considering our IV bolus of drug A  Let A0 decay to A0/2 and solve for t = t1/2  Then Ln(A0/2) = Ln(A0) – k * t1/2  Rearranging: k * t1/2 = Ln(A0) – Ln(A0/2)  Giving t1/2 = Ln2/k t1/2 = 0.693 / k  What happens to a drug? ADME  Absorption Absorption: The Process by which a drug moves from the site of administration to the site of action Quantified by the Absorption rate constant (A First Order Process) For Oral Absorption requires unique Properties Water Soluble in the gut Lipophilic for membrane permeation Water soluble in plasma Absorption can be solubility (dissolution rate) and pH (pKa) dependent Solubility is also pH dependent  Distribution It is the process by which a drug moves from the bloodstream into the peripheral tissues Driven by the relative affinity of binding for blood and tissue compartments Quantified by the Volume of Distribution (Vd) “The ratio between the amount of drug in the body and the amount in the plasma” Volume of Distribution = Total amount of drug dosed / Plasma concentration at t 0 Beaker 1 Beaker 2 Drug Distributed equally through liquid 90% of drug binds to beaker wall Drug Added: 1µg (1x10-6 g) Drug Added: 1µg (1x10-6 g) Drug Concentration: 1x10-8 g/mL (10 ng/ml) Drug Concentration: 1x10-9 g/mL (1 ng/ml) Vd = 1x10-6 g / 1x10-8 g/mL Vd = 1x10-6 g / 1x10-9 g/mL Vd = 100 mL Vd = 1000 mL  Volume of Distribution Volume of Distribution = Total amount of drug dosed / Plasma concentration at t 0 Rat 1 Rat 2 Drug Added: 10 Drug Added: 10 Drug Concentration in blood: 9 Drug Concentration in blood: 1 Vd = 10 / 8 = 1.2 Vd = 10 / 1 = 10 VOLUME OF DISTRIBUTION IS NOT A REAL VOLUME! The bigger the volume of distribution, the more it is distributing out of the blood  Calculating Volume of Distribution Dose of Drug A = 100mg At T0, [A]0 (Plasma Concentration of Drug A at T0) is: 20,000ng/ml 𝑉𝑑= 𝐷𝑜𝑠𝑒 𝐴/ 𝐴 0 Adjusting for Units 20,000ng/ml = 20,000ug/L 20,000ug/L = 20mg/L Then: Vd = 100mg / 20mg/L = 5L  Metabolism Metabolism is the irreversible chemical alteration of a drug by a biological system Drug Metabolism can happen in most organs and is covered by 2 Phases: Phase 1 Reactions: Introduces a new chemical group via: Oxidation Reactions Reduction Reactions Hydrolysis Reactions Aim: To produce Inactive metabolites Phase 2 Conjugation Reactions: Conjugates the molecule with charged chemical species via: Glucouronidation Acylation Sulfation Aim: To decrease lipophilicity and increase  Excretion Clearance is the efficiency of irreversible elimination of a drug from the systemic circulation and defined as the “Volume of blood cleared of drug per unit time” Important Considerations with Clearance  Can be limited by organ blood flow e.g. Hepatic Blood Flow  Can include saturable processes  Includes both metabolism and excretion  Clearance is additive Clearance is additive: ClTotal = ClHepatic + ClRenal + ClMetabolic  Calculating Clearance: Hepatic Clearance Clearance is dependent on the organs by which the body clears the drug. Main organ for drug clearance is the LIVER. 1. Enzymatic activity in the liver 2. Hepatic blood flow (Rate Limiting Step) Maximum hepatic clearance is equal to liver blood flow (Q) Therefore, if the total blood clearance is greater than liver blood flow (Q), there must be extra- hepatic clearance Liver involved in ‘first pass effect’; important for oral administration Calculating Clearance: Extra-hepatic Clearance Other organs may also contribute to clearance, another main example being the Kidney Extraction ratio and Blood flow for each organ determines the clearance by each organ Whole body clearance is the sum of all organ clearances CLTotal = CLHepatic + CLRenal = (0.28 + 0.88) = 1.16 L/min Important to consider the impact of drug/disease induced impairments of hepatic/renal function can change the pharmacokinetics of a drug  Bioavailability The first step for any drug is dependent on its ability to pass the membrane - absorption Bioavailability (F) defines the fraction of unchanged drug that reaches the systemic circulation. Therefore for IV dosing, F must always equal 1 (100%) For Oral Dosing, Bioavailability depends on: Absorption from the Gut Can be limited by gut/hepatic metabolism/excretion (If Eh=1 then F= 0%) Bioavailability is calculated using dose-adjusted AUCs of oral and iv dosing by: A drug can be 100% absorbed but still have zero bioavailability. WHY?  Key Equations to remember! 1. Relationship between half-life (t1/2) in hours and the elimination rate constant (k) (hours-1) t1/2 = 0.693 / k 2. Volume of distribution (Vd, Units: mL, L) 4. Oral Bioavailability (F, Units: %) 𝑉𝑑= 𝐷𝑜𝑠𝑒 𝐴/ 𝐴 0 3. Whole Body Clearance (Cl, Units: mL.min-1, L.h-1) 𝐶𝐿=𝑘∗ 𝑉𝑑 𝐶𝑙=𝑑𝑜𝑠𝑒∗ 𝐹 / 𝐴𝑈𝐶  Typical in vivo PK Experiments IV Bolus Dose Oral Dose  Administer a Fixed Dose  Administer a Fixed Dose  Take serial blood samples (Sometimes greater than IV)  Analyse drug plasma levels  Take serial blood samples  Analyse drug plasma levels  Calculating PK Parameters: In Vivo Experiments Intravenous (IV) bolus Oral Dosing  Directly administered into the plasma compartment  Dosed into the gastro-intestinal tract  Instantaneous distribution  Introduces a first-order absorption rate constant (ka)  Elimination  Absorption phase (Absorption rate > Elimination rate)  Cmax (Absorption rate = Elimination Rate)  Elimination Phase ( Elimination rate > Absorption Rate)  Calculating PK Parameters: Typical Readouts Intravenous (IV) bolus Oral Dosing  Half-life  Total Drug Exposure (AUC)  Elimination Rate Constant (k)  Bioavailability  Volume of Distribution  Clearance  Clearance  Half-life for Terminal elimination  Total Drug Exposure (AUC)  Cmax, Tmax Pharmacokinetics  Summary Pharmacokinetic Principles Rates of Reaction: First Order Kinetics Compartment models: single and multiple compartments Elimination Rate Constant and Half-Life ADME Absorption Distribution Metabolism Excretion Bioavailability Key Equations Used to Calculate Pharmacokientic Parameters Pharmacodynamics  Real-World PK/PD As Cladribine effects memory T cell production: As Midazolam acts as a reversible GABA agonist: Effects outlast plasma concentration of drug Effects more closely linked to plasma concentration of drug Mechanism of effect can have big implications on PK/PD Relationship