Pharmacokinetics Slides PDF

Pharmacokinetics Dr Martin Hawes Senior Lecturer Veterinary Pharmacology and Therapeutics Sunday, 08 September 2024 1  Learning Outcomes...

Pharmacokinetics Dr Martin Hawes Senior Lecturer Veterinary Pharmacology and Therapeutics Sunday, 08 September 2024 1  Learning Outcomes 1. Define the term pharmacokinetics and differentiate it from pharmacodynamics 2. Define peak concentration (Cmax), half-life (T½) time to peak concentration (tmax), AUC, therapeutic index, minimum effective concentration and minimum toxic concentration 3. Describe the concepts of steady state, volume of distribution and clearance 4. Describe and explain the differences between zero and first order kinetics 5. Describe one, two and multi-compartment models of drug distribution and elimination 6. Explain how to calculate dosing interval Sunday, 08 September 2024 2  Learning Objectives 1 - 2 Define the term pharmacokinetics and differentiate it from pharmacodynamics Define peak concentration (Cmax), half-life (T½) time to peak concentration (tmax), AUC, therapeutic index, minimum effective concentration and minimum toxic concentration  Naming medicines Pre-read Pharmacodynamics is what the drug does to the body Pharmacokinetics is what the body does to the drug Monday, 09 September 2024 4  Drug concentration-time profile of iv and oral doses What is the value of Cmax for this iv injection? 100 75 50 25 0 Monday, 09 September 2024 5  Drug concentration-time profile of iv and oral doses What is the value of tmax for this oral tablet? 0 0.5 1.0 1.5 2.0 2.5 3.0 Monday, 09 September 2024 6  MEC / MTC / Therapeutic Range Toxic effects Minimum Toxic Concentration CP - Plasma Therapeutic (MTC) Concentration range Minimum Effective Sub-optimal effect Concentration or no effect (MEC) Time Monday, 09 September 2024 7  Therapeutic Index Core concept: Therapeutic Index, a measure of drug safety, is the ratio between the dose/concentration of a drug producing toxicity and the dose/concentration that produces a therapeutic effect. The larger the therapeutic index, the more favourable the drug's margin of safety. In clinical studies, TI is calculated as the median dose of a drug that causes unacceptable toxicity for 50 % of the population (TD50) divided by the median effective dose for 50 % of the population (ED50), i.e. TI = TD50/ED50 In animal toxicology studies, TI is calculated as the lethal dose of a drug for 50 % of the population (LD50) divided by the minimum effective dose for 50 % of the population (ED50), i.e. TI = LD50/ED50 Sunday, 08 September 2024 8  Clinical case When administering a drug with a low therapeutic index, greater care needs to be taken to minimise drug toxicity, including monitoring its plasma concentration. Bruno has Stage C cardiac failure with risk of atrial fibrillation. He is managed at home and is on several drugs, including digoxin. Digoxin has a narrow therapeutic index. How frequently will you measure Bruno’s digoxin levels? What would trigger you to take additional drug levels? Sunday, 08 September 2024 9  Area under the curve The AUC is a measure of the overall exposure of the body to the drug, reflecting both the amount absorbed into the bloodstream and how long the drug stays in the system. We can use the AUC to assess a drug’s bioavailability Monday, 09 September 2024 10  Bioavailability (F) Core concept: Drug Bioavailability is the fraction of administered dose of the parent drug that reaches the systemic circulation. The bioavailability for an iv injection will be 100% iv injection F = AUCiv/Doseiv F = 100% Sunday, 08 September 2024 11  Bioavailability Bioavailability for an oral dosage form will be less than 100% Some drug not absorbed from GIT Effects of first-pass metabolism Oral drug F = AUCoral/Doseoral F < 100% Sunday, 08 September 2024 12  Bioavailability Bioavailability can be used to compare the absorption of different routes/formulations Absolute bioavailability, e.g. Fab = AUCoral/Doseoral compares the AUC of one AUCiv/Doseiv route of administration with that of the same drug given intravenously. Relative bioavailability, compares the AUC from one non-intravenous route of administration to another non-intravenous route. Sunday, 08 September 2024 13  SPC Example ‘After oral administration of therapeutic doses, amlodipine is well absorbed with peak plasma levels between 3 to 6 hours post dose. After a single dose of 0.25 mg/kg, absolute bioavailability is estimated to be 74% and the peak plasma level is 25 ng/ml, in fasted state. Absorption of amlodipine is not influenced by concomitant food intake in humans. Amlodipine tablet may be given with or without food to cats in clinical use.’ Sunday, 08 September 2024 14  Learning Objectives 3 Describe the concepts of steady state, volume of distribution and clearance  Volume of distribution (VD) Core concept: Volume of distribution is defined as the theoretical volume needed to dilute the total amount of drug in the body at a given time to achieve the measured plasma concentration. VD is an indication of the extent to which a drug is distributed to the tissues of the body. Drugs with large volumes of distribution are extensively distributed throughout the tissues of the body Drugs with a small volume of distribution are more restricted to the plasma. VD = D where D = administered dose CP CP = plasma concentration Taken from Rang & Dale (2016) Sunday, 08 September 2024 16  Volume of distribution (VD) VD = D where D = administered dose CP CP = plasma concentration Examples of VD (L/kg) for a 30 kg dog Meloxicam (0.3L/kg) 9 litres Digoxin (13.0L/kg) 390 litres Sunday, 08 September 2024 17  SPC Example ‘The volume of distribution is approximately 10 L/kg.’ Sunday, 08 September 2024 18  Clearance Core concept: Drug Clearance refers to the efficiency of drug elimination. Drug clearance is defined as the ratio of the rate of drug elimination (e.g. mg/h) to the concentration of drug in plasma (e.g. mg/L). Drug clearance can be considered as the volume of plasma that is completely cleared of drug per unit time (e.g. L/h). Overall drug clearance is the sum of hepatic clearance + renal clearance + clearance by other routes. Drug clearance is constant for most drugs – this is useful because it helps establish appropriate dosing (drug dosage/frequency of administration) Dose = Total clearance x Plasma concentration Bioavailability Sunday, 08 September 2024 19  Interpretation of clearance Drug clearance represents a flow of blood Volume of plasma cleared of drug per unit time (e.g. L/h) Clearance is therefore related to cardiac output Amount of Amount of drug in blood Kidneys drug in blood entering kidneys leaving kidneys Amount of drug cleared by the kidneys High mL/min/kg 85 51 41 30 28 26 20 Med mL/min/kg 37 22 17 13 12 11 8 Low mL/min/kg 12 7 6 4.3 4 3.8 3 Sunday, 08 September 2024 20  High, medium or low clearance? ‘Total plasma clearance in healthy cats is estimated to be 2.3 ml/min/kg.’ ‘Total plasma clearance [in dogs] …. is ….. 2.92 to 3.56 L/h/kg.’ (~ 50 ml/min/kg) Sunday, 08 September 2024 21  Drug concentration-time profile of oral dose Single dose CP - Plasma Concentration (µg/ml) Oral dose curve Time (h) Sunday, 08 September 2024 22  Drug concentration-time profile – repeated doses Sunday, 08 September 2024 23  Repeated dosing and steady state Core concept: Steady-State Concentration is the concentration of drug in the plasma reached when the rate of drug absorption is equal to the rate of drug elimination following repeated or continuous dosing. With repeated dosing the plasma concentration-time curve plateaus and a “steady-state” is reached Cmax Cmin Sunday, 08 September 2024 24  Steady state How will the steady state level change if: 1. You double the dose (same dosing interval)? 2. Same dose but half the dosing interval? 3. Large first dose then smaller maintenance doses? 4. The patient’s kidney function is reduced? Sunday, 08 September 2024 25  iv infusion For an iv infusion at steady state, the rate of elimination, kel (rate out), is equal to the infusion rate, k0 (rate in) Sunday, 08 September 2024 26  Loading dose The steady-state concentration can be reached more rapidly by administration of a loading dose at the start of therapy Sunday, 08 September 2024 27  Learning Objective 4 Describe and explain the differences between zero and first order kinetics Monday, 09 September 2024 28  Time for a pee !! Sunday, 08 September 2024 29  Time for a pee !! Full Empty Time Sunday, 08 September 2024 30  Zero and First Order Kinetics Core concept: Zero and first order kinetics refers to changes in the amount of drug as a function of time: zero-order refers to change by a constant amount per unit time, whereas first order refers to change by a constant fraction per unit time. Adapted from https://forum.facmedicine.com/threads/elimination-kinetics-first-and-zero-order-kinetics.25353/ Sunday, 08 September 2024 31  Zero and First Order Kinetics Zero Order Elimination – A constant amount of drug eliminated per unit of time. Regardless of the plasma concentration, the rate of elimination is constant First Order Elimination – A constant fraction of drug is eliminated per unit of time. As the concentration drops the elimination rate drops as well Most drugs follow first-order kinetics. When the drug is eliminated by first-order kinetics clearance is constant. Adapted from https://forum.facmedicine.com/threads/elimination-kinetics-first-and-zero-order-kinetics.25353/ Sunday, 08 September 2024 32  First order kinetics C0 First Order Elimination - The same proportion fraction of drug is eliminated per unit of time First Order Elimination Exponential curve CP = C0 e-kelt where: Cp is the amount of drug in the body at time t C0 is the initial amount of drug kel is the elimination constant Time (hrs) Sunday, 08 September 2024 33  First order kinetics Slope = -kel 2.303 kel = elimination constant Time (hrs) Sunday, 08 September 2024 34  Half-life (T½) Core concept: Drug elimination half-life (T½) is the time taken for the drug plasma concentration to decrease by 50% and is calculated during the elimination phase. T½ is constant when drug elimination follows first-order kinetics Sunday, 08 September 2024 35  Half-life and steady state How will the steady state peak and trough levels change if: 1. The drug has a long half-life? 2. The drug has a short half-life? Sunday, 08 September 2024 36  Multiple doses and steady state It takes approximately 5 half-lives to reach steady state Drug elimination half-life can vary between patients, as patient, drug and environmental factors (e.g., disease state and age- related physiological changes) can alter drug clearance Sunday, 08 September 2024 37  Learning Objective 5 One, two and multi-compartment models of drug distribution and elimination Monday, 09 September 2024 38  PK Models: One compartment model A compartment refers to those organs and tissues for which the rates of uptake and subsequent clearance are similar One compartment model - highly simplified model – drug is absorbed from its site of administration into a single central compartment Central Drug kab Drug kel compartment Very few drugs behave as simplistically as the single- compartment model Sunday, 08 September 2024 39  PK Models: Two-compartment models All drugs are distributed, to some extent, into tissues Two-compartment models describe the pharmacokinetics of most drugs Central Drug kab Drug kel Compartment 1 k1 to 2 k2 to 1 Peripheral Compartment 2 Taken from Rang & Dale (2016) Sunday, 08 September 2024 40  PK Models: Multi-compartment models The pharmacokinetics of some drugs are better described using more complex, multi-compartment models Central Drug kab Drug kel Compartment 1 k1 to 2 k2 to 1 k2 to 3 k2 to 4 Peripheral Peripheral Peripheral Compartment 3 Compartment 2 Compartment 4 k3 to 2 k4 to 2 Sunday, 08 September 2024 41  Learning Objective 6 Calculating the dosing interval Monday, 09 September 2024 42  Learning Objective 6 Calculating the dosing interval Using pharmacokinetic parameters Monday, 09 September 2024 43  Calculating dose interval Pharmacokinetic parameters can be used to generate appropriate dosing regimens for patients. Example – What should the dosing interval of amlodipine 0.125 mg/kg be to maintain a mean steady state plasma concentration of 25 ng/ml? (Bioavailability of amlodipine is 70%, and clearance is 2.5 ml/min/kg). τ= DxF where τ = Dosing interval D = Dose ClP x Css F = Bioavailability ClP = Clearance CSS = Steady state concentration τ = 125000 ng. kg-1 x 0.7 2.5 ml.min-1.kg-1 x 25 ng.ml-1 τ = 1400 mins τ = 23 hours - simplify to dose once a day Sunday, 08 September 2024 44  Calculating dose Example – What dose of Drug X should be given orally every 12 hours to maintain a steady state plasma level of 10 micrograms/ml? (Bioavailability of Drug X orally is 70% and clearance is 35 ml/kg/h). where Css = Steady state plasma concentration DOSE = CSS. ClP. T F = Bioavailability F ClP = Clearance T = Dosing interval DOSE = 0.01 mg.ml-1. 35 ml.kg-1.h-1. 12 h 0.7 DOSE = 6 mg/kg every 12 hours Sunday, 08 September 2024 45  Key Points LO - Define the term pharmacokinetics and differentiate it from pharmacodynamics Pharmacokinetics (PK) is the measurement and interpretation of changes in drug concentration in the body over time. PK follows the drug concentration-time course of drug absorption, distribution, metabolism and elimination (ADME): PK is what the body does to the drug Pharmacodynamics (PD) explores the relationship between drug concentration at the site of action and the resulting effects: PD is what the drug does to the body Sunday, 08 September 2024 46  Key Points LO - Define peak concentration (Cmax), time to peak concentration (tmax), therapeutic index, minimum effective concentration and minimum toxic concentration Cmax is the peak plasma concentration of a drug after administration tmax is the time to reach Cmax Minimum effective concentration (MEC) is the minimum plasma concentration required to produce therapeutic effect Minimum toxic concentration (MTC) is the minimum plasma concentration at which toxicity usually occurs Core concept: Therapeutic Index, a measure of drug safety, is the ratio between the dose/concentration of a drug producing toxicity and the dose/concentration that produces a therapeutic effect. Sunday, 08 September 2024 47  Key Points The area under the curve of the plasma concentration-time graph (AUC) reflects the amount of drug absorbed into the blood stream after administration (termed the exposure) Core concept: Drug Bioavailability is the fraction of administered dose of the parent drug that reaches the systemic circulation. Bioavailability of an iv injection is 100%. All other formulations will have a bioavailability less than 100%. Monday, 09 September 2024 48  Key Points LO - Describe the concepts of steady state, volume of distribution and clearance Core concept: Steady-State Concentration is the concentration of drug in the plasma reached when the rate of drug absorption is equal to the rate of drug elimination following repeated or continuous dosing. With equal doses given at a constant dosage interval, it takes approximately 5 half-lives to reach steady state Core concept: Volume of Distribution is the theoretical volume needed to dilute the total amount of drug in the body at a given time to achieve the measured plasma concentration. If the volume of distribution for a drug is greater than the value calculated for total body water, it suggests drug is concentrating into fat and tissue Sunday, 08 September 2024 49  Key Points LO - Describe the concepts of steady state, volume of distribution and clearance Core concept: Drug Clearance refers to the efficiency of drug elimination, defined as the ratio of the rate of drug elimination (e.g. mg/h) to the concentration of drug in plasma. (e.g. mg/L) Clearance can be considered as the volume of plasma cleared of drug per unit time. It is the sum of the clearance of drug from plasma effected by all organs, i.e. total clearance = renal clearance + hepatic clearance + lung clearance + …. Sunday, 08 September 2024 50  Key Points LO - Describe and explain the differences between zero and first order kinetics Core concept: Zero and first order kinetics refers to changes in the amount of drug as a function of time: zero-order refers to change by a constant amount per unit time, whereas first order refers to change by a constant fraction per unit time. With zero-order elimination, the rate of elimination is constant regardless of the plasma concentration With first-order elimination, the elimination rate falls as the concentration falls A log drug plasma concentration versus time plot will produce a straight line, the slope of which is related to the elimination rate constant, kel Sunday, 08 September 2024 51  Key Points LO – Define the half-life of a drug Core concept: Drug elimination half-life (T½) is the time taken for the drug plasma concentration to decrease by 50% and is calculated during the elimination phase. LO - Describe one, two and multi-compartment models of drug distribution and elimination A compartment refers to those organs and tissues for which the rates of uptake and subsequent clearance are similar In a one compartment model, drug is absorbed from its site of administration into a single central compartment Two-compartment models describe the PK of most drugs – the model comprises of a central and a peripheral compartment The behaviour of some drugs is best described using a multi- compartment model Sunday, 08 September 2024 52  Key Points LO - Explain how to calculate dosing interval Pharmacokinetic parameters, such as steady state, clearance, bioavailability etc. can be used to calculate appropriate dosing regimens for patients Sunday, 08 September 2024 53