Introduction To Biopharmaceutics & Pharmacokinetics PDF

INTRODUCTION TO BIOPHARMACEUTICS & PHARMACOKINETICS Course Instructor: Dr. Zara Sheikh Assistant Professor School of Pharmacy Pharmaceutics Pharmaceutics- Pharmaceutics is the general area of study concerned with the formulation, manufacture, stability and...

INTRODUCTION TO BIOPHARMACEUTICS & PHARMACOKINETICS Course Instructor: Dr. Zara Sheikh Assistant Professor School of Pharmacy Pharmaceutics Pharmaceutics- Pharmaceutics is the general area of study concerned with the formulation, manufacture, stability and effectiveness of pharmaceutical dosage forms. Biopharmaceutics ◻ Biopharmaceutics is the science that examines this interrelationship of the physicochemical properties of the drug, the dosage form in which the drug is given, and the route of administration on the rate and extent of systemic drug absorption (Bioavailability). ◻ Bio= life Pharmacokinetics ⚫ Pharmacokinetics- refers to what the Administration of body does to the drug and drug It involves the absorption, distribution, metabolism and excretion (ADME) of the drug. ⚫ Drug Disposition- Description of drug distribution and excretion is referred to as drug disposition. ⚫ Biopharmaceutics involves factors that influence- The stability of the drug within the drug product. The release of the drug from the drug product. The rate of dissolution/ release of the drug at the absorption site. The systemic absorption of the drug. Dynamic relationship between the drug, the drug product, and the pharmacologic effect ADME ⚫ Absorption- Absorption is defined as the process by which a drug proceeds from the site of administration to the site of measurement (usually blood, plasma or serum). ⚫ Distribution- The dispersion of a drug throughout fluids and tissues of the body. It is a reversible process. ⚫ Metabolism- The irreversible transformation of parent compounds to daughter compounds (also called biotransformation). ⚫ Excretion- Irreversible loss of drugs from the site of measurement. Excretion is the removal of drug from the body in an unchanged form/metabolite through various routes. Ex- urine, saliva, sweat, respiratory route, biliary secretion. Pharmacodynamics 📫 Pharmacodynamics refers to the relationship between drug concentration at the site of action and the pharmacological response, including biochemical and physiological effects that influence the interaction of the drug with the receptor. Process for reaching dosage decisions with therapeutic drug monitoring (TDM) Measurement of Drug Concentrations ⚫ Drug concentrations are measured in biologic samples, such as milk, saliva, plasma, and urine. ⚫ General analytical method used- Chromatography (HPLC)  Sampling of Biologic Specimens Two methods are used to take the sample of biological specimens: 1.Invasive methods include sampling blood, spinal fluid, synovial fluid, tissue biopsy, or any biologic material that requires parenteral or surgical intervention in the patient. 2.In contrast, noninvasive methods include sampling of urine, saliva, feces, expired air, or any biologic material that can be obtained without parenteral or surgical intervention. Sampling of Biologic Specimens Why should we measure drug/metabolite concentration in biological specimens? ◻ The measurement of drug and metabolite concentration in each of these biologic materials yields important information, such as 1. the amount of drug retained in, or transported into, that region of the tissue or fluid, 2. the likely pharmacologic or toxicologic outcome of drug dosing, 3. and drug metabolite formation or transport. Drug Concentration ◻ Drug Concentration in a compartment is defined as the amount of drug in a given volume, such as mg/L. Drug Concentrations in Blood, Plasma, or Serum ⚫ Measurement of drug concentration (levels) in the blood, serum, or plasma is the most direct approach to assessing the pharmacokinetics of the drug in the body. ⚫ Whole blood contains cellular elements including red blood cells, white blood cells, platelets, and various other proteins, such as albumin and globulins. In general, serum or plasma is most commonly used for drug measurement. Drug Concentrations in Blood, Plasma, or Serum Blood is the fluid most often sampled for determining drug concentration  Drug Concentrations in Blood, Plasma, or Serum ⚫ To obtain serum, whole blood is allowed to clot and the serum is collected from the supernatant after centrifugation. ⚫ Plasma is obtained from the supernatant of centrifuged whole blood to which an anticoagulant, such as heparin, has been added. ⚫ Therefore, the protein content of serum and plasma is not the same. ⚫ Plasma perfuses all the tissues of the body, including the cellular elements in the blood. Assuming that a drug in the plasma is in dynamic equilibrium with the tissues, then changes in the drug concentration in plasma will reflect changes in tissue drug concentrations.  Plasma Drug Concentration- Time Curve ◻ The plasma level–time curve is generated by obtaining the drug concentration in plasma samples taken at various time intervals after a drug product is administered. ◻ The concentration of drug in each plasma sample is plotted on rectangular-coordinate graph paper against the corresponding time at which the plasma sample was removed. ◻ As the drug reaches the general (systemic) circulation, plasma drug concentrations will rise up to a maximum.  Plasma Drug Concentration- Time Curve ⚫ Usually, absorption of a drug is more rapid than elimination. As the drug is being absorbed into the systemic circulation, the drug is distributed to Peak conc. all the tissues in the body and is also /window simultaneously being eliminated. ⚫ Elimination of a drug can proceed by excretion, biotransformation, or a plasm combination of both. a / Peak time ⚫ The relationship of the drug level– time curve and various pharmacologic parameters for the drug is shown in Figure 1. Figure 1: Plasma level – Time Curve Plasma Drug Concentration- Time Curve  Plasma Drug Concentration- Time Curve The MEC: the MEC reflects the minimum concentration of drug needed at the receptors to produce the desired pharmacologic effect. The MTC: the MTC represents the drug concentration needed to just barely produce a toxic effect. The onset time : It corresponds to the time required for the drug to reach the MEC. The intensity of the pharmacologic effect: It is proportional to the number of drug receptors occupied, which is reflected in the observation that higher plasma drug concentrations produce a greater pharmacologic response, up to a maximum. The duration of drug action: It is the difference between the onset time and the time for the drug to decline back to the MEC. Plasma Drug Concentration- Time Curve ⚫ The therapeutic window is the concentration between the MEC and MTC. ⚫ Drugs with a wider therapeutic window are generally considered safer than drugs with a narrow therapeutic window. ⚫ Sometimes the term therapeutic index is also used. ⚫ Therapeutic index refers to the ratio between the toxic and therapeutic dose. Plasma Drug Concentration- Time Curve ⚫ The peak plasma level (Cmax): The maximum concentration of drug in the plasma which is related to the dose, the rate constant for absorption, and the elimination constant of the drug ⚫ The time for peak plasma level (Tmax) is the time for maximum drug concentration in the plasma and is a rough marker of average rate of drug absorption. ⚫ AUC (area under curve) is the amount of drug systemically absorbed.  Biological ½ life ½ life = how much time it takes for plasma drug concentration to decrease to half of what it was at equilibrium (t1/2) Drug with shorter biological half life require more frequent dosing than drug with longer biological half life Volume of Distribution ⚫ Volume of Distribution is also known as Apparent volume of distribution, is used to quantify the distribution of a drug between plasma and the rest of the body after oral or parenteral dosing. ⚫ It is called as Apparent Volume because all parts of the body equilibrated with the drug do not have equal concentration. ⚫ It is defined as the volume in which the amount of drug would be uniformly distributed to produce the observed blood concentration. Volume of distribution ◻ Volume of distribution (Vd) is an important indicator of the extent of drug distribution into body fluids and tissues. ◻ Vd relates the amount of drug in the body (X) to the measured concentration in the plasma (C). ◻ Thus, Vd is the volume required to account for all of the drug in the body if the concentrations in all tissues are the same as the plasma concentration. Volume of Distribution ⚫ A large volume of distribution usually indicates that the drug distributes extensively into body tissues and fluids. ⚫ Conversely, a small volume of distribution often indicates limited drug distribution. ⚫ Volume of distribution indicates the extent of distribution but not the tissues or fluids into which the drug is distributing. ⚫ Two drugs can have the same volume of distribution, but one may distribute primarily into muscle tissues, whereas the other may concentrate in adipose tissues. Volume of distribution ◻ Approximate volumes of distribution for some commonly used drugs are shown in Table below. Imagine the body as a tank! Volume of distribution ◻ We can use the relationship given for volume, amount of drug administered, and resulting concentration to estimate a drug's volume of distribution in a patient. ◻ If we give a known dose of a drug and the concentration of that drug achieved in the plasma, we can calculate a volume of distribution. Case Study !!! ◻ If 500 mg of drug X is administered intravenously and the plasma concentration is determined to be 25 mg/L just after the dose is given, then volume of distribution= ??? ◻ If the first 80-mg dose of gentamicin is administered intravenously and results in a peak plasma concentration of 8 mg/L, volume of distribution is?  PLASMA DRUG CONCENTRATION VERSUS TIME CURVES ◻ With the one-compartment model, if we continuously measure the concentration of a drug in the plasma after an intravenous bolus dose and then plot these plasma drug concentrations against the times they are obtained, the curve would result as follows : ◻ Note that this plot is a curve and that the plasma concentration is highest just after the dose is administered, at time zero (t=0). ◻ Because of cost limitations and patient convenience in clinical situations, only a small number of plasma samples can usually be obtained for measuring drug concentrations. ◻ From these known values, we are able to predict the plasma drug concentrations for the times when we have no samples. In clinical situations, it is rare to collect more than two samples after a dose. Either take natural log or use semilog scale to plot the data Semilog paper  Task !! ⚫ A drug that follows a one-compartment model is given as an intravenous injection, and the following plasma concentrations are determined at the times indicated: ⚫ Using semilog graph paper, determine the approximate concentration in plasma at 6 hours after the dose. A. 18 mg/L B. 30 mg/L C. 10 mg/L; setting a plasma drug concentration of 5 mg/L lower therapeutic limit may result in reduced clinical efficacy. (1)What is the volume of distribution in a 20- year-old male patient weighing 70 kg? (2)What is the total dose for the patient if he is dosed at 5 mg/kg?  Practice Problem Ans. Solution - (1)Volume of distribution for the patient = 0.7 L/kg x 70 kg = 49 L (answer). (2) Dose for patient = 5 mg/kg x 70 kg = 350 mg (answer). Clearance ◻ Another important parameter in pharmacokinetics is clearance. ◻ Clearance is a measure of the removal of drug from the body. ◻ Plasma drug concentrations are affected by ✔the rate at which drug is administered, ✔ the volume in which it distributes and ✔ its clearance.  Clearance contd. ◻ Clearance (expressed as volume/time) describes the removal of drug from a volume of plasma in a given unit of time (drug loss from the body). ◻ Clearance does not indicate the amount of drug being removed. It indicates the volume of plasma (or blood) from which the drug is completely removed, or cleared, in a given time period.  Clearance contd. ◻ Drugs can be cleared from the body by many different mechanisms, pathways, or organs, including hepatic biotransformation and renal and biliary excretion.  Clearance contd. ◻ Total body clearance of a drug is the sum of all the clearances by various mechanisms.  Clearance contd. ⚫Let us consider a single well-perfused organ that eliminates drug. ⚫Blood flow through the organ is referred to as Q (mL/minute) , where ⮚ Cin is the drug concentration in the blood entering the organ and ⮚ Cout is the drug concentration in the blood exiting organ. ⚫ If the organ eliminates some of the drug, Cin > Cout ⚫We can measure an organ's ability to remove a drug by relating Cin and Cout. ⚫This extraction ratio (E): ⚫This ratio must be a fraction between 0 and 1. Organs that are very efficient at eliminating a drug will have an extraction ratio approaching 1 (i.e., 100% extraction). Clearance contd. ◻ The drug clearance of any organ is determined by blood flow and the extraction ratio: ◻ organ clearance = blood flow × extraction ratio ◻ If an organ is very efficient in removing drug (i.e., E= near 1) but blood flow is low, Cl will also be low ◻ Also, if an organ is inefficient in removing drug (i.e., E =close to 0) even if blood flow is high, clearance would again be low. ◻ Clearance can also be a useful parameter for constructing dosage recommendations in clinical situations. It is an index of the capacity for drug removal by the body organs. Clinical correlate ⚫Propranolol is a drug that is eliminated exclusively by. hepatic metabolism. ⚫ The extraction ratio for propranolol is greater than 0.9, so most of the drug presented to the liver is removed by one pass through the liver. ⚫Therefore, clearance is approximately equal to liver blood flow (Cl = Q × E: when E ~ 1.0, Cl ~ Q). ⚫One indication of the high extraction ratio is the relatively high oral dose of propranolol compared with the intravenous dose; an oral dose is 10-20 times the equivalent intravenous dose. ⚫The difference reflects the amount of drug removed by first-pass metabolism after absorption from the gastrointestinal tract and before entry into the general circulation. First order and zero order elimination ◻ Most drugs are eliminated by a first-order process ◻ The amount of drug eliminated in a set amount of time is directly proportional to the amount of drug in the body. ◻ For zero-order elimination, the amount of drug eliminated for each time interval is constant, regardless of the amount of drug in the body ◻ First order Fraction of drug eliminated over a given time remains constant ◻ Zero order Fraction of drug eliminated over a given time varies Time Amount Amount Fraction (Hrs) remainin eliminate eliminated g in the d body 0 1000 - - 1 850 150 0.15 2 700 150 0.176 4 550 150 0.214 5 400 150 0.273 Rates and Orders of Reactions Rate ◻ The rate of a chemical reaction of process is the velocity with which the reaction occurs. ◻ Consider the following chemical reaction: Drug A -------- > Drug B ◻ If the amount of drug A is decreasing with respect to time (that is, the reaction is going in a forward direction), then the rate of this reaction can be expressed as - dA dt Rates and Orders of Reactions ⚫ Since the amount of drug B is increasing with respect to time, the rate of the reaction can also be expressed as + dB dt ⚫ Usually only the parent (or pharmacologically active) drug is measured experimentally. The metabolites of the drug or the products of the decomposition of the drug may not be known or may be very difficult to quantitate. ⚫ The rate of a reaction is determined experimentally by measuring the disappearance of drug A at given time intervals. Rates and Orders of Reactions Rate constant: The rate constant is a proportionality factor in the rate law of chemical kinetics that relates the molar concentration of reactants to reaction rate. It is also known as the reaction rate constant or reaction rate coefficient and is indicated in an equation by k. A B; K=[B]/[A] Order of a reaction ◻ The order of a reaction refers to the way in which the concentration of drug or reactants influences the rate of a chemical reaction or process. Zero-Order Reactions ◻ If the amount of drug A is decreasing at a constant time interval t, then the rate of disappearance of drug A is expressed as dA/dt = - k0 (1) The term k0 is the zero-order rate constant and is expressed in units of mass/time (eg, mg/min). Zero-Order Reactions ◻ Integration of the Equation (1) yields the following expression: A = - k 0t + A 0 (2) where A 0 is the amount of drug at t = 0. ◻ Based on this expression, a graph of A versus t yields a straight line. ◻ The y intercept is equal to A0, and the slope of the line is equal to k 0. Zero-Order Reactions Zero-Order Reactions ◻ Equation (2) may be expressed in terms of drug concentration, which can be measured directly. C = - k 0t + C 0 where C 0 is the drug concentration at time 0, C is the drug concentration at time t, and k 0 is the zero-order decomposition constant. Mathematical Problem A pharmacist weighs exactly 10 g of a drug and dissolves it in 100 mL of water. The solution is kept at room temperature, and samples are removed periodically and assayed for the drug. The pharmacist obtains the following data. Find out the zero order rate constant (k0), slope. C0 =100 mg/mL C=90 mg/mL. t=4 hr C= - k0t + C 0 90= - k04 +100 k0= 100-90=10/4=2.5 mg/mL hr  First-Order Reactions ◻ If the amount of drug A is decreasing at a rate that is proportional to the amount of drug A remaining, then the rate of disappearance of drug A is expressed as dA = -kA (1) dt where k is the first-order rate constant and is expressed in units of time– 1 (eg, hr– 1). ◻ Integration of Equation (1) yields the following expression ln A = - kt + ln A0 (2) First-Order Reactions ◻ Equation (2) may also be expressed as A = A0 e-kt ◻ Because ln = 2.3 log, Equation (2) becomes log A = -kt + log A0 (3) 2.3 First-Order Reactions ◻ When drug decomposition involves a solution, starting with initial concentration C0, it is often convenient to express the rate of change in drug decomposition, dC/dt, in terms of drug concentration, C, rather than amount because drug concentration is assayed. ◻ Hence, dC = -kC (4) dt ln C = - kt + ln C0 (5) First-Order Reactions ◻ Equation (5) may be expressed as C = C0 e-kt ◻ Because ln = 2.3 log, Equation (5) becomes log C = -kt + log C0 (6) 2.3 First-Order Reactions ◻ According to Equation (3), a graph of log A versus t will yield a straight line, the y intercept will be log A0, and the slope of the line will be –k/2.3. ◻ Similarly, a graph of log C versus t will yield a straight line according to Equation (6). The y intercept will be log C0, and the slope of the line will be –k/2.3. First-Order Reactions Mathematical Problems 1. How many half-lives (t 1/2) would it take for 99.9% of any initial concentration of a drug to decompose? Assume first-order kinetics 2. If the half-life for decomposition of a drug is 12 hours, how long will it take for 125 mg of the drug to decompose by 30%? Assume first-order kinetics and constant temperature. 3. Exactly 300 mg of a drug are dissolved into an unknown volume of distilled water. After complete dissolution of the drug, 1.0-mL samples were removed and assayed for the drug. The following results were obtained: How many half-lives (t 1/2) would it take for 99.9% of any initial concentration of a drug to decompose? Assume first-order kinetics If the half-life for decomposition of a drug is 12 hours, how long will it take for 125 mg of the drug to decompose by 30%? Assume first- order kinetics and constant temperature. Differences between Zero order Kinetics and First order Kinetics Zero Order Kinetics First Order Kinetics ◻ Rate = k ◻ Rate = k C ◻ C = Co - kt ◻ C = Co e-kt ◻ C vs. t graph is ◻ C vs. t graph is NOT linear, decaying LINEAR exponential. Log C vs. t graph is linear.  Video for Zero, and First Order Reaction ◻ https://www.youtube.com/watch?v=2 LMdj91x2HA Half-Life ◻ Half-life (t 1/2) expresses the period of time required for the amount or concentration of a drug to decrease by one-half. First-Order Half-Life ◻ The t1/2 for a first-order reaction may be found by means of the following equation: t1/2 = 0.693 k  Zero-Order Half-Life ◻ In contrast to the first-order t1/2, the t1/2 for a zero- order process is not constant. ◻ The zero-order t1/2 is proportional to the initial amount or concentration of the drug and is inversely proportional to the zero-order rate constant k0: t1/2 = 0.5 A0 k0 ◻ Because the t1/2 changes as drug concentrations decline, the zero-order t1/2 has little practical value. Q. What is the difference between a rate and a rate constant? Ans. A rate represents the change in amount or concentration of drug in the body per time unit. For example, a rate equal to –5 mg/hr means the amount of drug is decreasing at 5 mg per hour. A positive or negative sign indicates that the rate is increasing or decreasing, respectively. Rates may be zero order, first order, or higher orders. For a first-order rate, the rate of change of drug in the body is determined by the product of the elimination rate constant, k, and by the amount of drug remaining in the body, ie, rate = – kDB, where k represents "the fraction" of the amount of drug in the body that is eliminated per hour. If k = 0.1 hr– 1 and DB = 10 mg, then the rate = 0.1 hr – 1 x 10 mg = 1 mg/hr. see Answer continued ◻ The rate constant in this example shows that one-tenth of the drug is eliminated per hour, whatever amount of drug is present in the body. For a first-order rate, the rate states the absolute amount eliminated per unit time (which changes with the amount of drug in the body), whereas the first-order rate constant, k, gives a constant fraction of drug that is eliminated per unit time (which does not change with the amount of drug in the body).  References ◻ Applied Biopharmaceutics and Pharmacokinetics – Leon Shargel, Sussana Wu-Pong, Andrew B.C. Yu, 6th Edition, Mc Graw Hill Inc. Chapter -1 and Chapter -2 ◻ Biopharmaceutics & Clinical Pharmacokinetics - Milo Gibaldi, 4"' edition, Le &Febiger, Philadelphia.