Week 31 Introduction to Clinical Pharmacokinetics

Clinical testing

Phase 1: Is it safe pharmacokinetics? (healthy subjects) 20-100 subjects Phase 2: Does it work in patients w disease? 100-200pts Phase 3: Does it work, double blind? 1000-6000 pts

Marketing

Phase 4: postmarketing surveillance After 20 years generics become available

Plasma concentration vs. site of action

Plasma concentration is proportional to the concentration at the site of action

Assumptions of clearance

The rate of delivery of plasma (containing drug) to the organ and the intrinsic ability of the organ to extract the drug (the extraction ratio) will determine clearance At steady-state, the drug removal is equal to the rate of drug administered (rate in=rate out)

When does a patent expire

20 years after filing of application During the marketing phase

For drugs that are eliminated primarily by the kidney..

(more than or equal to 60% of the administered dose) → renal dose adjustments (see the prescribing information) - CrCL 30-60 mL/min: minor dosage adjustments - CrCL 15-30 mL/min: moderate dose adjustments - CrCL < 15 mL/min: major dose adjustments

Pharmacokinetics

- "What the body does to the drug" - Absorption, Distribution, Metabolism, and Elimination (ADME) - Quantitative relationship between administered drug dosages and dosing regimens and the drug plasma and/or drug tissue concentrations - Determines how rapid and for how long the drug will appear at the target organ - Concentration versus time model

Pharmacodynamics

- "What the drug does to the body" - Quantitative relationship between plasma and/or tissue concentrations and the magnitude of the pharmacologic effect - Concentration versus effect model

All drugs administered into the human body will proceed through a common pathway:

- Absorption - Distribution - Metabolism - Elimination

Bioavailability

- The fraction of an administered dose that reaches the systemic circulation - IV injection gives 100% bioavailability (F=1) - Other routes of administration will give F < 1

General statements of equation of Vd

A large volume of distribution equates to a drug that has a high affinity for tissue sites of distribution: -the [serum] is very low relative to [tissue] (e.g. digoxin) -Lipophilic drugs that distribute to tissues have a large Vd (that may be so large that it exceeds the total body fluid, which is 42 liters in a standard 70 kg man) -Tissue binding increases the apparent vol of distrib A small volume of distribution equates to a drug that is mainly distributed in the vascular compartment: -The [serum] is high relative to the [tissue] (e.g. aminoglycoside antibiotics) -Drugs that are highly-water soluble have a small Vd because they are confined intravascularly -Plasma protein binding of drugs decrease the apparent Vd, In general, drugs bound to protein are not pharmacologically active

Hepatic adjustments most important

A similar assessment of liver function should be made for drugs that are metabolized hepatically In the absence of specific pharmacokinetic dosing guidelines for a medication, a Child-Pugh score equal to 8 to 9 is grounds for a moderate decrease (~25%) in initial daily drug dose for agents that are metabolized primarily (more than or equal to 60%) hepatically, and a score of 10 or greater indicates that a significant decrease in initial daily dose (~50%) is required for drugs that are metabolized mostly by the liver

Child-pugh score

A widely used clinical classification for liver disease that incorporates clinical signs and symptoms (ascites and hepatic encephalopathy), in addition to these three laboratory tests, can be used as an indicator of a patient's ability to metabolize drugs that are eliminated by the liver. A Child-Pugh score in excess of 10 suggests very poor liver function. As a general rule, patients with cirrhosis have the most severe decreases in liver drug metabolism. Patients with acute or chronic hepatitis often retain relatively normal or slightly decreased hepatic drug-metabolism capacity In the absence of specific pharmacokinetic dosing guidelines for a medication, a Child-Pugh score equal to 8 to 9 is grounds for a moderate decrease (~25%) in initial daily drug dose for agents that are metabolized primarily (more than or equal to 60%) hepatically, and a score of 10 or greater indicates that a significant decrease in initial daily dose (~50%) is required for drugs that are metabolized mostly by the liver

What is Clinical Pharmacokinetics?

Applies pharmacokinetic concepts in humans in order to design individualized dosage regimens that optimize the therapeutic response while minimizing adverse drug reactions

In vitro studies

Biologic products and chemical synthesis

Equation for clearance

CL= (rate of elimination of drug/ plasma drug concentration) Units=volume per unit time

Maintenance dose is dependent on what

Clearance In an elderly person who cannot renally clear needs to be maintenance dose

Clearance clinically

Clearance is the parameter that is responsible for the great interpatient variability observed in therapeutic drug monitoring Clearance is constant for a drug eliminated via first-order kinetics Clearance is NOT constant for a drug eliminated via zero-order kinetics The clearance of the great majority of drugs is relatively constant over a broad range of plasma concentrations (Cp). Since elimination rate is equal to clearance times plasma concentration, the elimination rate will be rapid at first and slow as the concentration decreases

Comparison of first and zero order elimination

Comparison of first-order and zero-order elimination. For drugs with first- order kinetics, rate of elimination (units per hour) is proportional to []; this is the more common process. In the case of zero-order elimination (right), the rate is constant and independent of []. First-order elimination kinetics: Elimination rate is not constant; t1/2 is constant Zero-order elimination kinetics: Elimination rate is constant; t1/2 is not constant

Are generics or brand names preferred?

Concern about the rising costs of healthcare have favored the use of generic drugs

What factors can alter clearance?

Depends on the drug dose, blood flow, and the condition of the organs of elimination (renal, hepatic, biliary, and other routes such as pulmonary) in the pt Other conditions such as cardiac disease and drugs that change blood flow may affect clearance

Medium Vd

Distributes evenly bw tissues and blood Moderate blood concentration

Large Vd

Distributes strongly into tissue Low blood concentration

Elimination

Drug elimination is NOT the same as drug excretion Drug elimination by metabolism may occur Generally, duration of action of many drugs is determined by the rate of elimination of the last dose of the drug (disappearance of the active molecules from the site of action, the bloodstream, and the body) The elimination of a drug from the body does NOT always end the effect. Irreversible inhibitors such as ASA will have an effect long after the drug is eliminated [platelet inhibitory effects last the lifetime of the platelet (~10 days) due to its irreversible inhibition of platelet COX-1 enzyme]

Distribution

Drug from the systemic circulation → organs and tissue

Absorption

Drug must be absorbed from its dosage form (e.g., oral - tablet, capsule, suspension, etc.) after administration In most situations, the drug needs to reach the systemic circulation in order to reach tissue site of its action (e.g., amiodarone needs to be absorbed from the GI tract when taken orally into the systemic circulation to reach the heart muscle so that it can decrease AV conduction) Bioavailability

Bioequivalence

Drug products are pharmaceutical equivalents if they contain the same active ingredients and are identical in strength or concentration, dosage form, and route of administration 2 pharmaceutically equivalent drug products are considered to be bioequivalent when the rates and extents of bioavailability of the active ingredient in the two products are not significantly different under suitable and identical test conditions → Can dispense generic in place of brand name A drug is called by its generic name (USAN - U.S. Adopted Name) or by its manufacturer's proprietary name (called trademark, trade name, or brand name) In most states, pharmacists are required by law to automatically substitute and dispense generic drugs rather than brand-name medications If you, as a physician, want to prescribe brand-name drugs in the outpatient setting, you need to indicate on the prescription, "do not substitute or brand name medically necessary" Sometimes substitution to generics is discouraged due to specialized release systems, narrow therapeutic indices, or substantial confusion on the part of patients that can lead to medication errors or noncompliance

What drugs follow zero order kinetics

Drugs such as aspirin, ethanol, and phenytoin exhibit zero-order kinetics

Animal testing

Efficacy, selectivety, mechanism Figure out toxins, teratogens, pharmacokinetics

Zero-order elimination and half life

Elimination rate is constant; t1/2 is not constant

First order elimination and half life

Elimination rate is not constant; t1/2 is constant

Rate and concentration in first order kinetics

Elimination rate is proportional to concentration If you increase the [], you increase the rate of elimination

Clearance

Expressed as volume/time (i.e., mL/min) Does NOT indicate the amount of drug removed Indicates the volume of plasma (or blood) from which the drug is completely removed or cleared in a given amount of time Relates the rate of elimination to the plasma concentration • Clt=Clr+Clm+Clb+Clother where - Clt is total body clearance (from all mechanisms) - Clr is renal clearance (through renal excretion) - Clm is clearance by liver metabolism or biotransformation - Clb is biliary clearance (through biliary excretion) - Clother is clearance by other routes such as pulmonary

Effects of therapeutic window

Faster absorption gets closer to MEC Larger dose gets closer to toxic and has a longer duration Faster elimination decreases the duration

What Factors Are Important to Consider in Determining Bioavailability?

First-pass hepatic metabolism Solubility of the drug Chemical instability Nature of the drug formulation

Subtherapeutic

Generally refers to blood levels below therapeutic levels due to insufficient dosing

What is the most important renal variable in drug elimination?

Glomerular filtration rate (GFR), and creatinine clearance (CrCL) is a convenient approximation of GFR.

Half life equation

Half life= (0.7 x Vd)/Clearance

Cardiac adjustments

Heart failure is often overlooked as a disease state that can alter drug disposition Severe heart failure decreases cardiac output and therefore reduces liver blood flow Theophylline, lidocaine, and drugs with high extraction ratios are compounds whose clearance declines with decreased liver blood flow Initial dosages of these drugs should be reduced in patients with moderate to severe heart failure (New York Heart Association class III or IV) by 25% to 50% until steady-state []s and response can be determined.

Solubility of the drug

Help determine bioavailability Very hydrophilic drugs are poorly absorbed because of their inability to cross the lipid- rich cell membranes. Paradoxically, drugs that are extremely hydrophobic are also poorly absorbed, because they are totally insoluble in aqueous body fluids and, therefore, cannot gain access to the surface of cells. For a drug to be readily absorbed, it must be largely hydrophobic, yet have some solubility in aqueous solutions. This is one reason why many drugs are weak acids or weak bases. There are some drugs that are highly lipid- soluble, and they are transported in the aqueous solutions of the body on carrier proteins such as albumin.

Chemical instability

Help determine bioavailability - Some drugs, such as penicillin G, are unstable in the pH of the gastric contents. Others, such as insulin, are destroyed in the GI tract by degradative enzymes.

Nature of the drug formation

Help determine bioavailability Drug absorption may be altered by factors unrelated to the chemistry of the drug. For example, particle size, salt form, crystal polymorphism, enteric coatings and the presence of excipients (such as binders and dispersing agents) can influence the ease of dissolution and, therefore, alter the rate of absorption.

First-pass hepatic metabolism

Help determine bioavailability When a drug is absorbed across the GI tract, it enters the portal circulation before entering the systemic circulation. If the drug is rapidly metabolized by the liver, the amount of unchanged drug that gains access to the systemic circulation is decreased. Many drugs, such as propranolol or lidocaine, undergo significant biotransformation during a single passage through the liver.

Pregnancy and lactation labeling rule (PLLR)

In 2015 the FDA replaced the former pregnancy risk letter categories on prescription and biological drug labeling with new information to make them more meaningful to both patients and healthcare providers The A, B, C, D and X risk categories, in use since 1979, are now replaced with narrative sections and subsections to include: Pregnancy (includes Labor and Delivery): Pregnancy Exposure Registry Risk Summary Clinical Considerations Data Lactation (includes Nursing Mothers) Risk Summary Clinical Considerations Data Females and Males of Reproductive Potential Pregnancy Testing Contraception Infertility

Infusion rate equation

Infusion Rate (k0): k0 = CL x Css(Css = steady state concentration)

Loading Dose (LD)

It takes 4 to 5 half-lives to achieve steady-state but sometimes a large dose is needed and given (often parenterally) at the start of therapy in order to achieve target concentration (effective blood levels) rapidly Advantage for using loading dose: Desirable in urgent situations such as cases for treatment of arrhythmias Disadvantages of using loading dose: If the dose is too large and the drug has a long t1/2, patient may be exposed to a toxic concentration of the drug

Loading dose equation

LD=CpxVd F (Cp = concentration in plasma or target plasma concentration at steady state; F = bioavailability)

Therapeutic index of penicillin

Large Don't really need to worry much about toxicities

Maintenance dose equation

MD = Cp x CL x Ʈ F Ʈ = dosage interval (time between doses), if not administered continuously

Volume of distribution (Vd)

Measurement of the apparent space in the body available to contain the drug (gives a rough account of where the drug goes in the body) In reality, it does not necessarily correspond to any specific physiologic volume or space Vd = Amount of drug in body = Dose of the drug (mg) Plasma concentration Plasma concentration (mg/mL) Vd is generally expressed in (L) or (L/kg)

Drug elimination: first order elimination kinetics

Most drugs in clinical use are eliminated by a first-order process (kinetics): rate falls as plasma level falls Linear Pharmacokinetics Rate of elimination is proportional to the concentration (ie, the higher the [], the greater the amount of drug eliminated per unit time) The amount of drug eliminated per unit time is a fixed fraction of the available drug If we plot the log of the concentration versus time, we get a linear relationship (right side of image below) The fraction of drug removed over time is constant. The slope of the line is the elimination rate and in first-order it is the same regardless of the concentration. Therefore it is called the elimination rate constant (ke)

What is zero order kinetics also known as

Non-linear Pharmacokinetics Saturable kinetics: Zero-order is due to drugs that saturate elimination mechanisms can lead to high therapeutic or toxic concentrations (i.e., small changes in dose can lead to large effect)

Continuous IV infusion

Rate of attainment of Css in plasma Goal is to get to steady state

Drug elimination: Zero-order elimination kinetics

Rate of elimination is constant regardless of plasma concentration (or amount in body). The amt of drug eliminated per unit of time is constant The ability of the body to eliminate the drug has an upper limit which cannot be exceeded (e.g., saturable metabolism as with ethanol) Follows the Michaelis-Menten kinetics for enzyme kinetics related to metabolism: drug-metabolizing reactions have reached Vmax (maximum rate of rxn)

Effect of infusion rate on the steady state concentration (Css) of drug in plasma

Rate of infusion and steady-state plasma concentration are directly proportionalIncreasing the rate of infusion → increases the Css → No change in t1/2 Steady state drug concentration is inversely proportional to the clearance of the drug: Anything that ↓ clearance (e.g. liver or kidney disease) ↑ Css Anything that ↑ clearance ↓Css

Rate of infusion and half-life

Regardless of rate of infusion, it will always take the same amount of time 4 to 5 half lives

How would intermittent dosing or continuous infusion dosing look for one drug?

Relationship between frequency of dosing and maximum and minimum plasma [] when a steady-state theophylline plasma level of 10 mg/L is desired. The smoothly rising black line shows the plasma concentration achieved with an intravenous infusion of 28 mg/h. The doses for 8-hour administration are 224 mg; for 24-hour administration, 672 mg. In each of the three cases, the mean steady-state plasma [] is 10 mg/L A smaller dose but more frequency

Adjusting the dosage when elimination is altered by disease

Renal disease or reduced cardiac output often reduces the clearance of drugs that depend on renal elimination Alteration of clearance by liver disease is less common but may also occur. Impairment of hepatic clearance occurs (for high extraction drugs) when liver blood flow is reduced, as in heart failure, and in severe cirrhosis and other forms of liver failure Bc it is important in the elimination of drugs, assessing renal function is important in estimating dosage in patients. The most important renal variable in drug elimination is glomerular filtration rate (GFR), and creatinine clearance (CrCL) is a convenient approximation of GFR.

Maintenance dose (MD)

Series of repetitive drug doses or continuous infusion to maintain steady-state concentration within the therapeutic window Takes about 4-5 half lives to get to steady state without loading dose

Therapeutic index of warfarin

Small Easier to reach unacceptable toxicity

Small Vd

Stays mainly in blood Blood concentration is high

Therapeutic index

TD50/ED50 Describes the relative safety of a drug The small the index, the less safe the drug (the easier to get to the toxic index)

Development and testing of a new drug

The development and testing process required to bring a new drug to market in the United States. Some requirements may be different for drugs used in life- threatening diseases In vitro studies Animal testing Clinical testing (3 phases) Marketing (phase 4)

ASA and elimination

The elimination of a drug from the body does NOT always end the effect. Irreversible inhibitors such as ASA will have an effect long after the drug is eliminated [platelet inhibitory effects last the lifetime of the platelet (~10 days) due to its irreversible inhibition of platelet COX-1 enzyme]

Mean acceptable toxicity

The minimum concentration needed to toxic effects

The Cockcroft-Gault equation

The most widely used method to estimate CrCL (in milliliters per minute) in adults (age 18 years or older) who are within ~30% of their ideal body weight and have stable renal function Other methods to determine estimated CrCL for obese adults and patients with rapidly changing renal function are available Cockcroft-Gault equation where BW is body weight (in kilograms), age is the patient's age (in years), 0.85 is a correction factor to account for lower muscle mass in women, and Scr is serum creatinine (in milligrams per deciliter)

Steady-state

The rate of drug administration = Rate of drug elim. The duration of time required to reach steady state is dependent on the elimination half-life and is independent of dose size and frequency of administration, assuming the drug is eliminated via first-order kinetics Mathematically, it takes > 7 half- lives to reach steady state. However, in the clinical setting, steady state is said to be reached after 4-5 half-lives (see table)

Elimination half life

The time necessary for the drug concentration in plasma to decrease by one-half Is constant with drugs of first-order elimination and regardless of the amount of drug in the body The [] of first-order drug in the blood will decrease by 50% for every half-life Zero-order kinetic drugs do NOT have a constant half-life (t1/2 is variable) The half-life and the elimination rate constant express the same idea - how quickly the drug is removed from the plasma. The relationship bw t1/2 and ke is mathematically expressed by: t1/2 = 0.693/ke

Therapeutic window

a drugs blood concentration range between its MEC and MTC

Hepatic adjusments

There is no single test that can estimate liver drug- metabolism capacity accurately, and those that are used do not always prove accurate High aminotransferase (aspartate aminotransferase [AST] and alanine aminotransferase [ALT]) and alkaline phosphatase concentrations usually indicate acute hepatic cellular damage and do not establish poor liver drug metabolism reliably Abnormal values for three tests that usually indicate that drugs will be metabolized poorly by the liver are high serum bilirubin concentration, low serum albumin concentration, and a prolonged prothrombin time. Bilirubin is metabolized by the liver, and albumin and clotting factors are manufactured by the liver, so aberrant values for all three of these tests are a more reliable indicator of abnormal liver drug metabolism As in any patient with or without liver dysfunction, initial doses are meant as starting points for dosage titration based on patient response and avoidance of adverse effects Bc there are no good markers of liver function, clinicians have come to rely on pharmacokinetic parameters derived in various patient populations to compute initial doses of drugs that are eliminated hepatically

Renal adjustments

When deciding on initial doses for drugs that are eliminated renally, the patient's renal function should be assessed The most common clinical way is to take a blood sample, measure the patient's serum creatinine concentration and convert this value into an estimated CrCL Creatinine is a by-product of muscle breakdown in the body so none of these estimation methods work well in patients with muscle disease, such as multiple sclerosis, or diseases that alter muscle mass, such as cachexia, malnutrition, cancer, or spinal cord injury Serum creatinine values alone should not be used to assess renal function because they do not include the effects of age, body weight, or gender For drugs approved after 2010, renal drug dosing adjustments may also include recommendations using estimated glomerular filtration rate (eGFR) in addition to est. CrCL The Modification of Diet in Renal Disease (MDRD) Study equation is one commonly used equation for this purpose: eGFR (mL/min/1.73 m2) = 175 × (Scr)-1.154 × (Age)-0.203 × (0.742 if female) × (1.212 if African American) Since est. CrCL and eGFR are not interchangeable, specific dosage guidelines for one test or the other should be followed Supplemental doses of some medications also may be needed for patients receiving hemodialysis if the drug is removed by the artificial kidney or for patients receiving hemoperfusion if the drug is removed by the hemofilter