Clinical Pharmacokinetics: Rational Dosing and the Time Course of Drug Action Part 1

Models of drug distribution and elimination blank compartment model: no movement of drug out of the beaker steep rise to maximum concentration followed by a plateau route of elimination is present a sharp rise to a maximum followed by a slow decay blank compartment model: distribution from blood to extracellular fluids and tissues (rapid equilibration) drug in blood drug in extravascular volume 1st compartment 2nd compartment distribution phase followed by the slower elimination phase Figure 3-2. Models of drug distribution and elimination. The effect of adding drug to the blood by rapid intravenous injection is represented by expelling a known amount of the agent into a beaker. The time course of the amount of drug in the beaker is shown in the graphs at the right. One compartment model assumes linear pharmacokinetics and immediate distribution and equilibration throughout the body. A) There is no movement of drug out of the beaker, so the graph shows only a steep rise to maximum followed by a plateau. B) A route of elimination is present, and the graph shows a slow decay after a sharp rise to a maximum. Because the level of material in the beaker falls, the "pressure" driving the elimination process also falls, and the slope of the curve decreases. This is an exponential decay curve. Two compartment model shows that once a drug enters the body elimination begins. C) Drug placed in the first compartment ("blood") equilibrates rapidly with the second compartment ("extravascular volume") and the amount of drug in "blood" declines exponentially (proportional to its value) to a new steady state. D) A more realistic combination of elimination mechanism and extravascular equilibration is illustrated. The resulting graph shows an early distribution phase followed by the slower elimination phase.

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AUC area under the plasma concentration-time curve AUC reflects the total body exposure to a dose of drug The concentration of drug in plasma is integrated over time The bioavailability of a drug determines its concentration in plasma Clearance may be estimated from AUC: CL = dose / Css │ bioavailability determines Css therefore, CL = dose / AUC Using the trapezoidal rule, the plasma concentration-time profile is divided into several trapezoids; the AUC is calculated by adding the area of these trapezoids. Trapezoid: A = (a+b)/2 x h Estimation of CL is a calculation; it is not the definition of clearance.

AUC area under the plasma concentration-time curve AUC reflects the total body exposure to a dose of drug The concentration of drug in plasma is integrated over time The bioavailability of a drug determines its concentration in plasma Clearance may be estimated from AUC: CL = dose / Css │ bioavailability determines Css therefore, CL = dose / AUC Using the trapezoidal rule, the plasma concentration-time profile is divided into several trapezoids; the AUC is calculated by adding the area of these trapezoids. Trapezoid: A = (a+b)/2 x h Estimation of CL is a calculation; it is not the definition of clearance.

Bioavailability is factored into oral dosing calculations. Verapamil EH 0.67 Expected oral bioavailability of verapamil Fverapamil = 1 - 0.67 = 0.33 33% Note: Considerable inter-patient variability; the actual oral bioavailability of verapamil varies from 20% to 35% dosing rate = Converting a patient from verapamil I.V. to oral form I.V. dose = 5 mg / hour = 120 mg / 24 hours oral dose = dose / Fverapamil oral dose = 120 mg / 0.33 oral dose = 360 mg / 24 hrs Verapamil is used in the management of angina, atrial fibrillation, and hypertension

Bioavailability is factored into oral dosing calculations. Verapamil EH 0.67 Expected oral bioavailability of verapamil Fverapamil = 1 - 0.67 = 0.33 33% Note: Considerable inter-patient variability; the actual oral bioavailability of verapamil varies from 20% to 35% dosing rate = Converting a patient from verapamil I.V. to oral form I.V. dose = 5 mg / hour = 120 mg / 24 hours oral dose = dose / Fverapamil oral dose = 120 mg / 0.33 oral dose = 360 mg / 24 hrs Verapamil is used in the management of angina, atrial fibrillation, and hypertension

Clearance of a drug is the factor that predicts the rate of elimination in relation to the drug concentration the rate of drug elimination is directly proportional to drug concentration when clearance is constant CL=RATE OF DRUG ELIMINATION/DRUG CONCENTRAION IN MEASURED FLUID

CL=

CLEARANCE total systemic clearance: CL=clrenal+clhepatic+clother Clearance depends on: the drug, the blood flow, and the condition of the organs of elimination in the patient CLEARANCE REMAINS CONSTANT OVER A RANGE OF CONCENTRATIONS ENCOUNTERED CLINICALLY WHEN METABOLIZING ENZYMES AND TRANSPORTERS ARE NOT SATURATED Elimination of drug from the body may involve processes occurring in the kidney, the lung, the liver, and other organs. For most drugs, clearance is constant over the concentration range encountered in clinical settings, ie, elimination is not saturable, and the rate of drug elimination

CLEARANCE REMAINS CONSTANT OVER A RANGE OF CONCENTRATIONS ENCOUNTERED CLINICALLY WHEN METABOLIZING ENZYMES AND TRANSPORTERS ARE NOT SATURATED Elimination of drug from the body may involve processes occurring in the kidney, the lung, the liver, and other organs. For most drugs, clearance is constant over the concentration range encountered in clinical settings, ie, elimination is not saturable, and the rate of drug elimination

half life equation The time required for the amount of drug in the body or blood to fall by 50%. For drugs eliminated by first-order kinetics, a constant fraction is eliminated regardless of the concentration. Units: time

(0.7 x Vd) / CL

Multicompartment model (first-order kinetics) Central compartment: the highly blank tissues Final compartment: the more slowly blank tissues Building on the previous slide: Pharmacokinetic two-compartment model divided the body into central and peripheral compartment. The central compartment consists of the plasma and tissues where the distribution of the drug is practically instantaneous. The peripheral compartment consists of tissues where the distribution of the drug is slower. After one I.V. bolus injection (into the central compartment), the drug distributes into the peripheral compartment and is eliminated from the central compartment. Thus, the concentration decreases rapidly at first. Distribution into the peripheral compartment continues until the free concentration in the central compartment (plasma) is equal to the concentration in the peripheral compartment (tissues). The net flow of drug out the plasma along the concentration gradient continues until a steady-state - equilibrium - is reached. As the drug is continuously eliminated, the concentration gradient is created in the reverse direction - and drug flows out of the tissues into the plasma. The concentrations in both compartments decrease proportionally as elimination from plasma continues.

Central compartment: the highly perfused tissues Final compartment: the more slowly perfused tissues Building on the previous slide: Pharmacokinetic two-compartment model divided the body into central and peripheral compartment. The central compartment consists of the plasma and tissues where the distribution of the drug is practically instantaneous. The peripheral compartment consists of tissues where the distribution of the drug is slower. After one I.V. bolus injection (into the central compartment), the drug distributes into the peripheral compartment and is eliminated from the central compartment. Thus, the concentration decreases rapidly at first. Distribution into the peripheral compartment continues until the free concentration in the central compartment (plasma) is equal to the concentration in the peripheral compartment (tissues). The net flow of drug out the plasma along the concentration gradient continues until a steady-state - equilibrium - is reached. As the drug is continuously eliminated, the concentration gradient is created in the reverse direction - and drug flows out of the tissues into the plasma. The concentrations in both compartments decrease proportionally as elimination from plasma continues.

Clearance is the most important concept to consider when designing a rational regimen for long-term drug administration. The clinician usually wants to maintain steady-state concentrations of a drug within a therapeutic window or range associated with therapeutic efficacy and a minimum of toxicity for a given agent. (G&G Drug clearance is concerned with the rate at which the active drug is removed from the body; and for most drugs at steady state, clearance remains constant so that drug input equals drug output. Clearance is defined as the rate of drug elimination divided by the plasma concentration of the drug.Oct 15, 2013

Clearance is the most important concept to consider when designing a rational regimen for long-term drug administration. The clinician usually wants to maintain steady-state concentrations of a drug within a therapeutic window or range associated with therapeutic efficacy and a minimum of toxicity for a given agent. (G&G

Extent of drug absorption contributes to bioavailability 1) incomplete blank, 2) active efflux of blank dose, and / or 3) intestinal blank decrease blank incomplete release of drug from dosage formulation lesser ability of drug to cross physiologic barriers efflux of drug by P-glycoprotein metabolism in the intestinal epithelium

Extent of drug absorption contributes to bioavailability 1) incomplete absorption, 2) active efflux of oral dose, and / or 3) intestinal metabolism decrease Fmax incomplete release of drug from dosage formulation lesser ability of drug to cross physiologic barriers efflux of drug by P-glycoprotein metabolism in the intestinal epithelium

Illustration of Hepatic Extraction (EH) of a Drug First-pass effect (blue line) blank of drug in the gut (unabsorbed or metabolized) blanks of drug to metabolism in the liver before it enters the blankcirculation Rate of drug elimination from the circulation = Q × (Cin - Cout) / Cin The liver is the primary organ of biotransformation. It is considered the major "metabolic clearing house" for both endogenous chemicals (e.g., cholesterol, steroid hormones, fatty acids, and proteins) and xenobiotics. The liver has: Large blood flow; Portal circulation directly from gut to liver; Sinusoidal fenestrations (small blood vessels having pores in the endothelial cells that allow for rapid exchange of molecules); High concentration of metabolic enzymes; High concentration of transporters. The concept of extraction capacity is drug-specific. By knowing the liver's extraction capacity of a particular drug, the clinician will be able to evaluate the conditions affecting the organ that will change that drug's clearance and will be able to adapt the dosage regimen accordingly. The extraction of drug from the circulation by the liver is equal to blood flow (Q) times the difference between entering and leaving drug concentration, ie, Q × (Ci - Co). CL, clearance.

First-pass effect (blue line) Loss of drug in the gut (unabsorbed or metabolized) Loss of drug to metabolism in the liver before it enters the systemic circulation Rate of drug elimination from the circulation = Q × (Cin - Cout) / Cin

Equivalency between Drug Products blank equivalence: Drug products that contain the same active ingredients and are identical in strength or concentration, dosage form, and route of administration blank: The active ingredient in pharmaceutically equivalent drug products show no significant difference in the rate and extent of absorption of the active pharmaceutical ingredient blank blank: Pharmaceutically equivalent (and bioequivalent) drug products having similar safety and efficacy profiles. blankr: Biological product highly similar to an FDA-approved biological product and having no clinically meaningful differences in safety and effectiveness from the reference product blank blank product: Biosimilar to an FDA-approved reference product and meets additional standards for interchangeability. An interchangeable biological product may be substituted for the reference product by a pharmacist without the intervention of the health care provider who prescribed the reference product

Pharmaceutical equivalence: Drug products that contain the same active ingredients and are identical in strength or concentration, dosage form, and route of administration Bioequivalence: The active ingredient in pharmaceutically equivalent drug products show no significant difference in the rate and extent of absorption of the active pharmaceutical ingredient Therapeutic equivalence: Pharmaceutically equivalent (and bioequivalent) drug products having similar safety and efficacy profiles. Biosimilar: Biological product highly similar to an FDA-approved biological product and having no clinically meaningful differences in safety and effectiveness from the reference product Interchangeable biological product: Biosimilar to an FDA-approved reference product and meets additional standards for interchangeability. An interchangeable biological product may be substituted for the reference product by a pharmacist without the intervention of the health care provider who prescribed the reference product

Renal Extraction: Fraction of drug excreted in the urine Renal clearance is affected by: Renal blood flow, protein binding, function of nephrons Glomerular filtration rate Secretion rate from peritubular fluid into tubular fluid Reabsorption from tubular fluid back into the blood stream

Renal clearance is affected by: Renal blood flow, protein binding, function of nephrons Glomerular filtration rate Secretion rate from peritubular fluid into tubular fluid Reabsorption from tubular fluid back into the blood stream

Bioavailability (F) the fraction of active drug that reaches the systemic circulation The extent of bioavailability is determined by the: 1) blank and 2) blankn (F) of the dose that is absorbed and escapes first-pass elimination

The extent of bioavailability is determined by the: 1) Dose and 2) Fraction (F) of the dose that is absorbed and escapes first-pass elimination

Apparent Volume of Distribution V=Dose/Cp relates the amount of drug in the body to the concentration of drug in the blood or plasma Model considers the body as a single homogeneous compartment All drug admin goes directly into the central compartment Distribution is instantaneous throughout the volume Clearance is first-order Variable - age, gneder, body composition, disease (Apparent) Volume of distribution (Vd) relates the amount of drug in the body to the concentration of drug (C) in blood or plasma. Concentration provides the link between pharmacokinetics and pharmacodynamics and is the focus of the target concentration approach to rational dosing. Drugs with very high volumes of distribution have much higher concentrations in extravascular tissue than in the vascular compartment, ie, they are not homogeneously distributed. Drugs that are completely retained within the vascular compartment, on the other hand, have a minimum possible volume of distribution equal to the blood component in which they are distributed, eg, 0.04 L/kg body weight or 2.8 L/70 kg (Table 3-2) for a drug that is restricted to the plasma compartment.

relates the amount of drug in the body to the concentration of drug in the blood or plasma Model considers the body as a single homogeneous compartment All drug admin goes directly into the central compartment Distribution is instantaneous throughout the volume Clearance is first-order Variable - age, gneder, body composition, disease (Apparent) Volume of distribution (Vd) relates the amount of drug in the body to the concentration of drug (C) in blood or plasma. Concentration provides the link between pharmacokinetics and pharmacodynamics and is the focus of the target concentration approach to rational dosing. Drugs with very high volumes of distribution have much higher concentrations in extravascular tissue than in the vascular compartment, ie, they are not homogeneously distributed. Drugs that are completely retained within the vascular compartment, on the other hand, have a minimum possible volume of distribution equal to the blood component in which they are distributed, eg, 0.04 L/kg body weight or 2.8 L/70 kg (Table 3-2) for a drug that is restricted to the plasma compartment.