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Pharmacokinetics: A Refresher

Pharmacokinetics: A Refresher
Curtis L. Smith, Pharm.D., BCPS
Ferris State University Lansing, Michigan

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Pharmacokinetics: A Refresher

Learning Objectives: 1. Identify and provide examples using basic pharmacokinetic concepts commonly used in clinical practice, including elimination rate constant, volume of distribution, clearance, and bioavailability. 2. Describe specific pharmacokinetic characteristics of commonly used therapeutic agents, including aminoglycosides, vancomycin, phenytoin, and digoxin, as well as pharmacokinetic alterations in patients with renal and hepatic disease. 3. Define important issues as they pertain to drug concentration sampling and interpretation.

C. The maximum concentration (Cmax) is about 3.8 mg/L. D. The Vd is about 11.6 L. 3. R.O. is a 74-year-old woman initiated on gentamicin 100 mg intravenously every 24 hours for pyelonephritis. On admission, her serum creatinine (SCr) is 1.8 mg/dL. She also has congestive heart failure and is fluid overloaded because of her diminished renal function and nonadherence to her angiotensin-converting enzyme inhibitor and diuretic. A few days into her hospitalization, her SCr is down to 1.1 mg/dL, and she is reinitiated on furosemide and enalapril. Which one of the following most likely happened to the gentamicin t1/2 in R.O. during her hospitalization? A. Her clearance increased, which increased her Vd and decreased her t1/2. B. Her clearance increased, which increased her elimination rate constant and decreased her t1/2. C. Her Vd decreased, which increased her clearance and decreased her t1/2. D. Her Vd decreased, which increased her elimination rate constant and increased her t1/2. 4. A patient receives vancomycin 1000 mg intravenously every 24 hours and has a trough concentration, drawn 30 minutes before the next dose, of 6 mg/L. Which one of the following regimens is best for this patient if the goal trough concentration is 1015 mg/L? A. Maintain the dose at 1000 mg intravenously every 24 hours. B. Lower the dose to 500 mg, but keep the interval at every 24 hours. C. Keep the dose at 1000 mg, but shorten the interval to every 12 hours. D. Lower the dose to 500 mg, and shorten the interval to every 12 hours. 5. A 40-year-old, 60-kg woman who smokes presents to the emergency department at 2:00 pm with an acute exacerbation of asthma. She takes theophylline sustained release 300 mg 2 times/day, with the last dose taken at 9:00 that morning. Her theophylline concentration soon after presenting to the emergency department is 7.0 mg/L. She is stabilized and is to be sent home on theophylline

Self-Assessment Questions: Answers and explanations to these questions may be found at the end of this chapter. 1. J.H., a 65-year-old woman (65 kg), was recently initiated on tobramycin and piperacillin/tazobactam for treatment of hospital-acquired pneumonia. After the first dose of tobramycin 120 mg (infused from noon to 1:00 pm), serum tobramycin concentrations are drawn. They are 4.4 mg/L at 3:00 pm and 1.2 mg/L at 7:00 pm. Which one of the following is the best assessment regarding calculating tobramycin pharmacokinetic parameters in this patient? A. There are sufficient data to determine the half-life (t1/2) but not the volume of distribution (Vd). B. There are sufficient data to determine both the t1/2 and Vd. C. There are insufficient data to determine either the t1/2 or the Vd. D. There are sufficient data to determine the Vd but not the t1/2. 2. P.L. is a 60-year-old woman (60 kg) recently initiated on gentamicin and clindamycin. After the first gentamicin dose of 110 mg (infused from 6:00 pm to 6:30 pm), serum gentamicin concentrations are drawn. They are 3.6 mg/L at 7:30 pm and 0.9 mg/L at 11:30 pm. Which one of the following is the best assessment of this patients gentamicin pharmacokinetic parameters? A. The t1/2 is about 2 hours. B. The t1/2 is about 3 hours.

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sustained release. Which one of the following options is the best regimen for this patient? A. Theophylline sustained release 300 mg by mouth every 12 hours. B. Theophylline sustained release 600 mg by mouth every 12 hours. C. Theophylline sustained release 400 mg by mouth every 8 hours. D. Theophylline sustained release 600 mg by mouth every 8 hours. 6. L.R. is a 49-year-old patient with diabetes mellitus and renal failure. He was recently in a car accident and sustained head trauma. He currently receives phenytoin 100 mg intravenously 3 times/day, and his most recent concentration was 5.6 mcg/mL. You are asked to suggest a new dose to achieve a concentration within the therapeutic range. Laboratory results include sodium 145 mEq/L, potassium 3.9 mEq/L, chloride 101 mEq/L, carbon dioxide 26 mEq/L, blood urea nitrogen (BUN) 95 mg/dL, SCr 5.4 mg/dL, glucose 230 mg/dL, and albumin (Alb) 2.8 g/dL. Which one of the following choices is the best recommendation? A. Increase the dose to 200 mg intravenously 3 times/day. B. Increase the dose to 200 mg intravenously 2 times/day. C. Decrease the dose to 100 mg intravenously 2 times/day. D. Keep the dose the same. 7. You are asked how the TDx (fluorescence polarization immunoassay) and EMIT (enzyme multiplied immunoassay technique) assays compare with each other. Which one of the following statements is most accurate? A. Although both are immunoassays, one labels antibody, whereas the other labels antigen. B. Although both are immunoassays, one uses antibody as a marker, whereas the other uses a radioisotope. C. Although both are immunoassays, one uses an enzyme label, whereas the other uses a fluorescent label. D. They are both names for the same assay technique.

8. An elderly patient is seen in the morning medicine clinic for a routine follow-up. Medication history includes digoxin 0.25 mg/day by mouth, furosemide 40 mg/day by mouth, and potassium chloride 10 mEq/day by mouth. All doses were last taken at 8:00 am today at home. The patient has vague complaints of stomach upset, which began 2 days ago, but is otherwise in no apparent distress. A serum digoxin concentration drawn today at 10:00 am is 2.5 mcg/L. Which one of the following statements best describes what should be done next? A. Admit the patient for administration of digoxin Fab. B. Tell the patient to skip tomorrows dose of digoxin and begin 0.125 mg/day by mouth. C. Administer a dose of activated charcoal. D. Do nothing today about the digoxin. 9. A research group is analyzing the relationship between various independent patient demographics (e.g., age, height, weight, Alb, creatinine clearance [CrCl]) and phenytoin pharmacokinetics. Which one of the following is the best statistical test to use in assessing the relationship? A. B. C. D. One-way analysis of variance. Analysis of covariance. Multiple logistic regression. Spearman rank correlation.

10. N.T. is a 24-year-old woman receiving valproic acid for tonic-clonic seizures. Her most recent trough valproic acid concentration was 22 mg/L. Her most recent Alb concentration was 4.1 g/dL. Given this serum concentration, which one of the following recommendations is best regarding her dose? A. Continue with the current dose; the concentration is close enough to the therapeutic range. B. Assess adherence and increase her dose; the concentration is below the therapeutic range. C. Decrease her dose; the concentration is slightly above the therapeutic range. D. Assess adherence and then check a free valproic acid concentration and adjust accordingly.

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Patient Cases 1. H.R. is receiving vancomycin for a methicillin-resistant Staphylococcus aureus bacteremia. H.R. has chronic renal failure. A 1-g intravenous dose of vancomycin is given at noon on March 21. A concentration drawn at 2:00 pm on March 21 is 23.8 mcg/mL. A concentration drawn at 2:00 pm on March 24 is 12.1 mcg/mL. If you were to give a dose at 4:00 pm on March 24 and your goal trough concentration was 1015 mg/L, which one of the following represents the best time to give the next dose? A. B. C. D. 1 day after the dose on the 24th. 3 days from the dose on the 24th. 6 days from the dose on the 24th. There is insufficient information to calculate when to re-dose.

2. After the administration of 100 mg of a drug intravenously and 200 mg of the same drug by mouth, the areas under the curves are 50 and 25 mg/L/hour. Which one of the following best describes the bioavailability of this drug? A. 25%. B. 37.5%. C. 50%. D. 100%. 3. L.B. is receiving tobramycin for a resistant Pseudomonas aeruginosa pneumonia. L.B. has chronic renal failure. A loading dose of 160 mg is given at noon over 1 hour. A concentration is drawn at 6:00 pm, which is 6.5 mg/L, and again at 6:00 am the next day, which is 5.4 mg/L. When L.B.s concentration is 1 mg/L, which one of the following will be the best dose to achieve a peak of 9 mg/L? A. B. C. D. 140 mg. 160 mg. 180 mg. 200 mg.

I. Basic pharmacokinetic relationships Table 11 has definitions of terms. A. Absorption F = doseiv * AUCev doseev * AUCiv

B. Distribution F * dose Rapid intravenous (or oral) bolus: Vd = Cp0 Continuous intravenous infusion at steady state: Vd = R0 k * Css R0 C*k (1 ekti) and C = R0 Vd * k (1 ekti)

Continuous intravenous infusion before steady state:

Vd =

Multiple intravenous bolus at steady state:

Vd =

dose Css max * (1 e k)

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Multiple intermittent intravenous infusion at steady state: Vd = Css max = R0 * (1 - ekt) Vd * k * (1 - ek) Css min = Css max * ek(-t)

R0 k

1 ekt' Cmax (Cmin * ekt')

C. Clearance Clearance = dose AUC k= C1

Vd

k=

(1nC1 lnC2) (t2 t1)

t = 1/2 R0

0.693 k

Continuous intravenous infusion at steady state:

clearance =

Css
R0 * (1 ekti)

Continuous intravenous infusion before steady state:

clearance =

Multiple intravenous (or oral) bolus at steady state: (1nCmax lnCmin) C1 = C0 * ekt = k

clearance =

F * dose / Css avg

II. Absorption A. First-Pass Effect 1. Blood that perfuses virtually all the gastrointestinal tissues passes through the liver by means of the hepatic portal vein. a. Fifty percent of the rectal blood supply bypasses the liver (middle and inferior hemorrhoidal veins). b. Drugs absorbed in the buccal cavity bypass the liver. 2. Drugs affected most by the first-pass effect are those with a high hepatic extraction ratio. 3. Example Amitriptyline Desipramine Diltiazem Doxepin Imipramine Isosorbide dinitrate Labetalol Lidocaine Metoprolol Morphine Nicardipine Nifedipine Nitroglycerin Pentazocine Propoxyphene Propranolol Verapamil

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B. Enterohepatic Recirculation 1. Drugs are excreted through the bile into the duodenum, metabolized by the normal flora in the gastrointestinal tract, and reabsorbed into the portal circulation. 2. Occurs with drugs that have 1) biliary (hepatic) elimination and 2) good oral absorption 3. Drug is concentrated in the gallbladder and expelled on sight, smell, or ingestion of food. Table 1. Examples of Compounds Excreted in Bile and Subject to Enterohepatic Cycling Compound Chloramphenicol Digoxin Estrogens Imipramine Indomethacin Nafcillin Rifampin Sulindac Testosterone Tiagabine Valproic acid Vitamin A Entity in Bile Glucuronide conjugate Parent Parent Parent and desmethyl metabolite Parent and glucuronide Parent Parent Glucuronides of parent and metabolites Conjugates Glucuronide conjugate Glucuronide conjugates Conjugates

Patient Case 4. Which one of the following statements best describes P-glycoprotein? A. B. C. D. It is a plasma protein that binds basic drugs. It transfers drugs through the gastrointestinal mucosa, increasing absorption. It diminishes the effect of cytochrome P450 (CYP) 3A4 in the gastrointestinal mucosa. It is an efflux pump that decreases gastrointestinal mucosal absorption.

C. P-glycoprotein 1. P-glycoprotein is an efflux pump (located in the esophagus, stomach, and small and large intestines) that pumps drugs back into the gastrointestinal lumen; it is a more important factor in drug absorption drug interactions than intestinal CYP3A4. 2. Both CYP3A4 and P-glycoprotein are located in small intestinal enterocytes and work together to decrease the absorption of xenobiotics. 3. Most CYP3A4 substrates are also P-glycoprotein substrates. 4. Many CYP3A4 inhibitors/inducers also inhibit/induce P-glycoprotein, leading to increases or decreases in bioavailability. 5. Examples of P-glycoprotein absorption drug interactions include verapamil or amiodarone or dronedarone and digoxin or dabigatran; rifampin or St. Johns wort and human immunodeficiency virus protease inhibitors or dabigatran.

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III. Distribution A. Definition: Apparent VdProportionality constant that relates the amount of drug in the body to an observed concentration of drug B. Protein Binding Table 2. Common Proteins Involved in Drug Protein Binding Protein Albumin -1-acid glycoprotein Lipoprotein Types of Drugs Bound Acidic Basic Lipophilic and basic Molecular Weight 65,000 44,000 200,0003,400,000 Normal Concentrations (g/L) (mol) 3550 500700 0.41.0 923 Variable Variable

C. P-glycoprotein 1. Functions as an efflux pump on the luminal surface of the blood-brain barrier, limiting entry to the central nervous system 2. It may be especially important with opioidsInduction of P-glycoprotein by chronic use of opioids may decrease the opioid effect (tolerance). 3. P-glycoprotein is also found in tumor cells, resulting in the efflux of chemotherapeutic agents from the cell and, ultimately, multidrug resistance.

IV. CLearance

Table 3. Enzymes Involved in Drug Metabolism Oxygenases CYPs Monoamine oxygenases Alcohol dehydrogenases Aldehyde dehydrogenases Xanthine dehydrogenases Conjugating enzymes Uridine diphosphateglucuronyl transferases Glutathione S -transferase Acetyltransferases Methyltransferases
CYP = cytochrome P450.

Hydrolytic enzymes Esterases Amidases Epoxide hydrolases Dipeptidases

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Table 4. Drug Transport Proteins Transport Protein Superfamily SLC Transport Protein (Gene [Protein]) SLC01A2 [OATP-A] Location and Function Hepatocyte: Bile acid uptake Drugs Affected by Transport Protein Digoxin Levofloxacin Methotrexate Statins Pravastatin Rifampin Valsartan Digoxin Fexofenadine Rifampin Statins Salicylatea Methotrexatea Zidovudinea Tetracyclinea Organic anions and cationsb Fexofenadine Glyburide Statins Cephalexin Captopril Enalapril Valacyclovir Metformin Pravastatin Glucuronide, sulfate, and glutathione metabolitesa Methotrexatea Pravastatina Rifampina See text

SLCO1B1 [OATP1B1]

Hepatocyte: Hepatic uptake of drugs

SLCO1B3 [OATP1B3]

Hepatocyte: Hepatic uptake of drugs

SLC22A1, SLC22A2, SLC22A6, SLC22A8 [OAT and OCT]

Hepatocyte: Hepatic uptake of drugsa Renal tubule (interstitial side): Secretion of drugsb

SLCO2B1 [OATP2B1]

Hepatocyte: Hepatic uptake of drugs

SLC15A1, SLC15A2 [PEPT1, PEPT2]

Renal tubule Intestinal enterocytes

ABC

SLC47A1, SLC47A2 [MATE1, MATE2-K] ABCB11 [BSEP] ABCC2, 3, 4, and 5 [MRP2, 3, 4, and 5]

Renal tubule Hepatocyte: Bile acid excretion into bile Hepatocyte: Excreting water-soluble drugs and metabolites into blooda Renal tubule (luminal side): Secretion of drugs Hepatocyte: See text in handout Renal tubule (luminal side): See text in handout Hepatocyte

ABCB1 [MDR1] (P-glycoprotein) ABCB4 [MDR3]

ABCG2 [BCRP]

Hepatocyte: Biliary excretion

Digoxin Paclitaxel Vinblastine Daunorubicin Doxorubicin Imatinib Methotrexate Mitoxantrone Statins

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Patient Case 5. A renal transplant patient receiving cyclosporine receives a diagnosis of community-acquired pneumonia. The patient is admitted to the hospital and initiated on ceftriaxone and a macrolide. A physician asks you to choose a macrolide that will not interact with the patients cyclosporine. Which one of the following macrolides is the best choice to meet the physicians criteria? A. Erythromycin. B. Clarithromycin. C. Azithromycin. D. All macrolides inhibit CYP3A4.

A. Cytochrome P450 1. Introduction a. A group of heme-containing enzymes responsible for phase 1 metabolic reactions b. Characteristic absorbance of light at 450 nm (thus, CYP) c. Primarily located in the membranes of the smooth endoplasmic reticulum in 1) liver, 2) small intestine, and 3) brain, lung, and kidney d. Encoded by a supergene family and subfamily; separate genes code for different isoenzymes e. Drugs will generally have a high affinity for one particular CYP, but most drugs also have secondary pathways.

CYP 3 A 4
specific enzyme subfamily (> 70% identical in amino acid sequence) family (> 40% identical in amino acid sequence) GENE for mammalian cytochrome

Figure 1. Nomenclature

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2. Distribution of CYP isoenzymes in human liver


1A2 13% 2E1 7% 2A6 4% 2D6 2% 3A4 36% 1A2 11% 2E1 4%

Other 26%

2B6 3% 2A6 3%

2D6 19% 3A4 30% 2C 18% 2C19 8%

2C9 16%

Content

Role in CYP-Mediated Drug Elimination

Figure 2. Distribution of CYP isoenzymes in human liver 3. Distribution of CYP isoenzymes in human gastrointestinal tract
Other CYPs 30%

CYP3A4 70%

Figure 3. Distribution of CYP isoenzymes in human gastrointestinal tract

4. Characteristics of CYP metabolism a. Inhibition is substrate-independent. b. Some substrates are metabolized by more than one CYP (e.g., TCAs [tricyclic antidepressants], SSRIs [selective serotonin reuptake inhibitors]). c. Enantiomers may be metabolized by a different CYP (e.g., warfarin). d. Differences in inhibition may exist within the same class of agents (e.g., fluoroquinolones, azole antifungals, macrolides, calcium channel blockers, H2 blockers). e. Substrates can also be inhibitors (e.g., erythromycin, verapamil, diltiazem). f. Most inducers and some inhibitors can affect more than one isozyme (e.g., cimetidine, ritonavir, fluoxetine, erythromycin). g. Inhibitors may affect different isozymes at different doses (e.g., fluconazole inhibits CYP2C9 at doses of 100 mg/day or greater, and inhibits CYP3A4 at doses of 400 mg/day or greater).
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B. P-glycoprotein 1. P-glycoprotein is an efflux pump that pumps drugs into the bile; the clinical effect of P-glycoprotein drug interactions in the bile is unknown. 2. P-glycoprotein pumps drugs from renal tubules into the urine; it also potentially limits the degree of reabsorption. 3. Examples of drug interactions: Quinidine/digoxin, cyclosporine/digoxin, and propafenone/digoxin C. Pharmacogenetics/Polymorphic Drug Metabolism 1. Population in general is divided into poor, extensive, and ultrarapid metabolizers; therefore, metabolism is considered polymorphic. 2. Definition of polymorphism: Coexistence of more than one genetic variant (alleles), which are stable components in the population (more than 1% of population) 3. Clear antimode results

No. of Patients

antimode

PM

EM

URM

Metabolic ratio of unchanged drug to metabolite (increasing metabolic capacity) Figure 4. Distribution of Patients in a Drug that Follows Polymorphic Metabolism
EM = extensive metabolizer; PM = poor metabolizer; URM = ultrarapid extensive metabolizer.

4. Phenotype: Expression of the trait; interaction of gene with environment a. Manifestation of the trait clinically b. Not necessarily constant 5. Genotype: Genetic makeup

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Table 5. Metabolic Pathways Demonstrating Polymorphism Pathway Oxidation Substrate Debrisoquine, dextromethorphan Enzyme CYP2D6 Drug Examples Tertiary amines Fluoxetine Flecainide Propafenone Metoprolol Propranolol Timolol Codeine Tamoxifen Amitriptyline Phenytoin Warfarin Clopidogrel Tertiary amines (diazepam) Phenytoin Omeprazole Clonazepam Dapsone Hydralazine Inamrinone Procainamide Sulfonamides

Oxidation Oxidation

Warfarin Mephenytoin

CYP2C9 CYP2C19

Acetylation

Isoniazid, caffeine

N-acetyltransferase

CYP = cytochrome P450.

V. NONLINEAR PHARMACOKINETICS

Patient Case 6. C.M. is a 55-year-old man who is initiated on phenytoin after a craniotomy. His current steady-state phenytoin concentration is 6 mg/L at a dose of 200 mg/day by mouth. If his affinity constant (Km) is calculated to be 5 mg/L, which one of the following is most likely to occur if the dose is doubled (to 400 mg/day by mouth)? A. B. C. D. His concentration will double because phenytoin clearance is linear above the K m. His concentration will more than double because phenytoin clearance is nonlinear above the K m. His concentration will stay the same because phenytoin is an autoinducer, and clearance increases with time. His concentration will increase by only 50% because phenytoin absorption decreases significantly with doses greater than 300 mg.

A. Michaelis-Menten Pharmacokinetics velocity = Vmax * S Km + S

Vmax = capacity constant (amount/time) Km = affinity constant (amount/volume) S = substrate concentration (amount/volume)

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B. Nonlinear Elimination 1. Saturation or partial saturation of the elimination pathway rate of elimination (dose) = Vmax * C Km + C

Vmax = maximum rate of elimination (amount/time) Km = concentration where elimination is Vmax (affinity constant) C = drug concentration 2. Note: Nonlinearity occurs when concentration is at or above Km. Example: Phenytoin a. Vmax normal = 7 mg/kg/day b. Km normal = 5.6 mg/L c. 50% variability between individuals

VI. Non-compartmental Pharmacokinetics A. Why Non-compartmental Pharmacokinetics? 1. Identification of the correct model is often impossible. 2. A compartmental view of the body is unrealistic. 3. Linear regression is unnecessaryit is easier to automate analysis. 4. Requires fewer and less stringent assumptions 5. More general methods and equations 6. There is no need to match all data sets to the same compartmental model. B. Definitions 1. Zero momentconcentration versus time curve Area under the curve (AUC) AUC = (Cn+1 + Cn) 2 * (tn+1 tn) ... + Clast

k 2. First momentconcentration * time versus time curve Area under the first moment curve (AUMC) AUMC = *

(Cn+1 * tn+1 + Cn * tn) 2

* (tn+1 tn) +

Clast * tlast k

Clast k2

3. Mean residence time (MRT) MRT = AUMC AUC

4. Mean absorption time (MAT) MAT = MRTev MRTiv

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C. Pharmacokinetic Parameter Estimation 1. Clearance clearance = dose AUC

2. Volume of distribution at steady state Vss = dose * AUMC AUC2

3. Elimination rate constant k= 1 MRT

4. Absorption rate constant ka = 1 MAT

5. Bioavailability F= Div * AUCev Dev * AUCiv

VII. data Collection and Analysis

Patient Case 7. R.K. is a 54-year-old woman with a history of diabetes mellitus and end-stage renal disease. She is receiving gentamicin for Pseudomonas aeruginosa pneumonia. A gentamicin concentration is ordered after dialysis. Which one of the following is the best approach to obtaining this sample? A. Obtain the concentration immediately after hemodialysis. B. Wait a few hours to obtain the concentration because it will decrease significantly within the first few hours after hemodialysis. C. Wait a few hours to obtain the concentration because it will increase significantly within the first few hours after hemodialysis. D. Wait until the next day so that all the effects of hemodialysis have abated.

A. Timing of Collection 1. Ensure completion of absorption and distribution phases (especially digoxin and vancomycin, etc.). 2. Ensure completion of redistribution postdialysis (especially aminoglycosides). B. Specimen Requirements 1. Whole blood: Use anticoagulated tube. Examples: Cyclosporine, amiodarone 2. Plasma: Use anticoagulated tube and centrifuge; clotting proteins and some blood cells are maintained. 3. Serum: Use red top tube, allow to clot, and centrifuge. Examples: Most analyzed drugs including aminoglycosides, vancomycin, phenytoin, and digoxin

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Patient Case 8. A drug assay is touted as having high specificity but low sensitivity. Which one of the following statements best describes what this means? A. The assay will not be able to distinguish the drug from like products, but it will be able to detect extremely low concentrations. B. The assay will not be able to distinguish the drug from like products, and it will not be able to detect extremely low concentrations. C. The assay will be able to distinguish the drug from like products and will be able to detect extremely low concentrations. D. The assay will be able to distinguish the drug from like products but will not be able to detect extremely low concentrations.

C. Assay Terminology 1. Precision (reproducibility): Closeness of agreement among the results of repeated analyses performed on the same sample a. Standard deviation (SD): Average difference of the individual values from the mean b. Coefficient of variation (CV): SD as a percentage of the mean (relative rather than absolute variation)

CV =

SD Mean

2. Accuracy: Closeness with which a measurement reflects the true value of an object Correlation coefficientStrength of the relationship between two variables 3. Predictive performance (accuracy) Precision: a.k.a. root mean squared error (RMSE)

N 1 MSE = pei2 N i=1

RMSE = mse

Bias: a.k.a. mean prediction error (ME)

N ME = 1 pei N i=1
Prediction error (pe) is the prediction minus the true value. 4. Sensitivity: Ability of an assay to quantitate low drug concentrations accurately; usually the lowest concentration an assay can differentiate from zero 5. Specificity (cross-reactivity): Ability of an assay to differentiate the drug in question from like substances

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D. Assay Methodology 1. Immunoassays a. Radioimmunoassay i. Advantages: Extremely sensitive (picogram range) ii. Disadvantages: Radioimmunoassay kits have limited shelf life because of the short t1/2 of labels, nuclear waste, and cross-reactivity. Clinical use for assaying digoxin and cyclosporine b. Enzyme immunoassay; ex. EMIT (enzyme multiplied immunoassay technique) c. Fluorescence immunoassay: TDx (Abbott) (fluorescence polarization immunoassay): Most common therapeutic drug monitoring assay i. Advantages: Simple, automated, highly sensitive, and stable reagents ii. Disadvantages: Background interference attributable to endogenous serum fluorescence 2. High-pressure liquid chromatography 3. Gas chromatography-mass spectrometry and liquid chromatography-mass spectrometry 4. Flame photometry 5. Bioassay E. Population Pharmacokinetics in Therapeutic Drug Monitoring 1. Population pharmacokinetics useful when: a. Drug concentrations are obtained during complicated dosing regimens. b. Drug concentrations are obtained before steady state. c. Only a few drug concentrations are feasibly obtained (limited sampling strategy). 2. Bayesian pharmacokinetics a. Prior population information is combined with patient-specific data to predict the most probable individual parameters. b. When patient-specific data are limited, there is greater influence from population parameters; when patient-specific data are extensive, there is less influence. c. With small amounts of individual data, Bayesian forecasting generally yields more precise results.

Patient Cases 9. K.M., an 80-year-old white woman (52 kg, 54), is admitted to the hospital for pyelonephritis with sepsis. She has a history of myocardial infarction 2, congestive heart failure, hypertension, osteoporosis, rheumatoid arthritis, and cerebrovascular accident. On admission, her BUN is 11 mg/dL, SCr is 0.92 mg/dL, and Alb is 2.9 g/dL. K.M. is initiated on the following drugs: trimethoprim/sulfamethoxazole intravenously, 240 mg of trimethoprim every 12 hours, lisinopril 10 mg/day by mouth, digoxin 0.125 mg/day by mouth, furosemide 40 mg/day by mouth, cimetidine 400 mg by mouth 2 times/day, acetaminophen 650 mg by mouth every 6 hours, calcium carbonate 500 mg by mouth 3 times/day, and carvedilol 6.25 mg by mouth 2 times/ day. Which one of the following is the best estimate of K.M.s glomerular filtration rate (GFR)? A. B. C. D. 10 mL/minute/1.73m 2. 30 mL/minute/1.73m 2. 60 mL/minute/1.73m 2. 120 mL/minute/1.73m 2.

10. Which one of K.M.s drug combinations is most likely to alter her SCr concentrations? A. B. C. D. Lisinopril and digoxin. Trimethoprim/sulfamethoxazole and cimetidine. Furosemide and calcium carbonate. Acetaminophen and carvedilol.

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VIII. Pharmacokinetics in Renal Disease A. Estimation of GFR/CrCl 1. Creatinine production and elimination a. Creatine is produced in the liver. b. Creatinine is the product of creatine metabolism in skeletal muscle. c. Creatinine is filtered at the glomerulus, where it undergoes limited secretion. d. Creatinine is useful in approximating GFR because i. At normal concentrations of creatinine, secretion is low. ii. The creatinine assay picks up a non-creatinine chromogen in the blood but not in the urine. 2. CrCl calculation to estimate GFR CrCl is calculated from a 24-hour urine collection and the following equation: CrCl (mL/minute) = Normal CrCl Healthy young men = 125 mL/minute/1.73m2 Healthy young women = 115 mL/minute/1.73m2 After age 30, 1% of GFR is lost per year. 3. Creatinine clearance estimation to estimate GFR a. Factors affecting SCr concentrations: i. Sex ii. Age iii. Weight/muscle mass iv. Renal function. Caveats: Creatinine clearance estimations worsen as renal function worsens (usually an overestimation). b. Jelliffe 98 0.8 (age 20) CrCl (mL/minute/1.73m2) = SCr Women: Use 90% of the above equation. Limitations: Serum creatinine concentration must be stable. Adults aged 2080 years Controversy: Rounding up SCr in patients with low concentrations (less than 0.71 mg/dL) c. Cockcroft and Gault CrCl (mL/minute) = (140 age) * (TBW) 72 * SCr volume of urine/1440 minutes urine creatinine concentration serum creatinine concentration

Women: Use 85% of the above equation. Use IBW in patients with BMI greater than 30 kg/m2. Ideal body weight (IBW) (men) = 50 kg + 2.3 kg for each inch over 5 feet IBW (women) = 45.5 kg + 2.3 kg for each inch over 5 feet

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Pharmacokinetics: A Refresher

Limitations: Serum creatinine concentration must be stable. Developed for adults only Not corrected for creatinine standardization (results in lower estimations) Controversy: Rounding up SCr in patients with low concentrations (less than 0.71 mg/dL) d. Modification of Diet in Renal Disease study equation Full equation: GFR (mL/minute/1.73m2) = 161.5 * (SCr)-0.999 * (age in years)-0.176 * 1.180 (if patient is African American) * 0.762 (if patient is a woman) * (BUN)-0.170 * (Alb)+0.318 Simplified four-variable equation: GFR (mL/minute/1.73m2) = 175 * (SCr)-1.154 * (age in years)-0.203 * 1.212 (if patient is African American) * 0.742 (if patient is a woman) These equations directly estimate GFR (NOT CrCl) and were developed using standardized creatinine concentrations. ii. These equations are recommended by the American Kidney Foundation and the European Renal Association to estimate renal function. iii. Not as accurate when GFR is greater than 60 mL/minute/1.73m2 iv. If used for drug dosing, convert value from milliliter per minute per 1.73m2 to milliliter per minute. v. If used for drug dosing and significantly different from Cockcroft and Gault, use clinical judgment and optimize risk versus benefit. e. Chronic Kidney Disease Epidemiology Collaboration equation (CKD-Epi) i. These equations directly estimate GFR (not CrCl). ii. These equations are more accurate than Modification of Diet in Renal Disease at higher GFRs (i.e., greater than 60 mL/minute/1.73m2). Table 6. Chronic Kidney Disease Epidemiology Collaboration equations Race and Sex Serum Creatinine (mg/dL) Equation African American Female < 0.7 GFR = 166 * (SCr/0.7)-0.329 * (0.993)Age > 0.7 GFR = 166 * (SCr/0.7)-1.209 * (0.993)Age Male < 0.9 GFR = 163 * (SCr/0.9)-0.411 * (0.993)Age > 0.9 GFR = 163 * (SCr/0.9)-1.209 * (0.993)Age White or other Female < 0.7 GFR = 144 * (SCr/0.7)-0.329 * (0.993)Age > 0.7 GFR = 144 * (SCr/0.7)-1.209 * (0.993)Age Male < 0.9 GFR = 141 * (SCr/0.9)-0.411 * (0.993)Age > 0.9 GFR = 141 * (SCr/0.9)-1.209 * (0.993)Age
GFR = glomerular filtration rate; SCr = serum creatinine.

i.

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f. Pediatric formulas. Do not round up low SCr values in pediatric patients. Schwartz CrCl (mL/minute) =

K * ht (cm) SCr

Table 7. Schwartz Equation Constants Age Low birth weight 1 year Full term 1 year 1 year to adolescence Muscular adolescent males K 0.33 0.45 0.55 0.7

Note: K = 0.413 for 1 year to adolescence when using standardized creatinine concentrations (other K values have not been updated)

Shull CrCl (mL/minute/1.73m2) =

(0.035*age(yrs) + 0.236) * 100 SCr

This is only for those aged 118 years. 4. Factors influencing CrCl estimates a. Patient characteristics i. Age ( production of creatinine with age) ii. Female sex ( production of creatinine) iii. Race (production of creatinine in African Americans) b. Disease states/clinical conditions i. Spinal cord injuries ( muscle mass; creatinine) ii. Amputations ( muscle mass; creatinine) iii. Cushing syndrome ( muscle mass; creatinine) iv. Muscular dystrophy ( muscle mass; creatinine) v. Guillain-Barr syndrome ( muscle mass; creatinine) vi. Rheumatoid arthritis ( muscle mass; creatinine) vii. Liver disease ( creatine; creatinine) viii. Glomerulopathic disease (greater amount of creatinine secretion in relation to filtration) c. Diet i. High-meat protein diets ( creatinine ingestion) ii. Vegetarians ( creatinine ingestion) iii. Protein-calorie malnutrition ( creatinine ingestion) d. Drugs/endogenous substances i. Laboratory interaction: Kinetic alkaline picrate method (a) Noncreatinine chromogens: In blood but not in urine (b) Cephalosporins (esp. cefoxitin): Chromogenic causing false elevations that are much greater in urine than blood (c) Acetoacetate (increased in fasting individuals, patients with diabetic ketoacidosis): Chromogenic causing false elevations ii. Pharmacokinetic interaction: Drugs compete with creatinine for renal secretion (causing false elevations), trimethoprim, cimetidine, fibric acid derivatives (other than gemfibrozil), and dronedarone.
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B. Drug Dosing in Renal Disease 1. Loading dose a. In general, no alteration is required, but it should be given to hasten achievement of therapeutic drug concentrations. b. Alterations in loading dose must occur if the Vd is altered secondary to renal dysfunction. Example: Digoxin 2. Maintenance doseAlterations should be made in either the dose or the dosing interval. a. Changing the dosing interval: i. Use when the goal is to achieve similar steady-state concentrations. ii. Less costly iii. Ideal for limited-dosage forms (i.e., oral medications) b. Changing the dose: i. Use when the goal is to maintain a steady therapeutic concentration. ii. More costly c. Changing the dose and the dosing interval: i. Often required for substantial dosage adjustment with limited-dosage forms ii. Often required for narrow therapeutic index drugs with target concentrations (a) If a drug is given more than once daily, then adjust the interval. (b) If a drug is given once daily or less often, then adjust the dose.

Patient Case 11. S.J. is a 55-year-old man with hepatic dysfunction and fungemia caused by Candida krusei. He has a small amount of ascites but is not encephalopathic. He is initiated on caspofungin, and the package insert states that doses should be decreased in patients with a Child-Pugh score of 79. If he has the following hepatic laboratory values, which one of the following best estimates his Child-Pugh score? Aspartate transaminase = 85 U/L, alanine transaminase = 56 U/L, alkaline phosphatase = 190 U/L, total bilirubin = 1.8 mg/dL, Alb = 2.9 g/dL, lactic dehydrogenase = 270 U/L, prothrombin time/international normalized ratio = 14.6/1.7, -glutamyl transferase = 60 U/L A. 3. B. 5. C. 8. D. 11.

IX. Pharmacokinetics in Hepatic Disease A. Dosage Adjustment in Hepatic Disease 1. Clinical response is the most important factor in adjusting doses in hepatic disease. 2. Low hepatic extraction ratio drugs a. Adjustment of maintenance dose is necessary only when hepatic disease alters Clint. b. Alterations in protein binding alone do not require alteration of maintenance dose, even though total drug concentrations decline. c. Loading doses may require reduction.

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3. High hepatic extraction ratio drugs a. Intravenous administration i. Usually necessary to decrease maintenance dose rate ii. Consider effect of hepatic disease on protein binding. b. Oral administration: Usually necessary to decrease maintenance dose rate B. Rules for Dosing in Hepatic Disease 1. Hepatic elimination of high extraction ratio drugs is more consistently affected by liver disease than low extraction ratio drugs. 2. The clearance of drugs that are exclusively conjugated is not substantially altered in liver disease. Table 8. Child-Pugh Classification for Liver Disease 1 0 0 < 1.5 > 3.5 04 Points 2 1 or 2 + 1.52.3 2.83.5 46 3 3 or 4 ++ > 2.3 < 2.8 >6

Encephalopathy Ascites Bilirubin (mg/dL) Alb (g/dL) Prothrombin time (seconds over control)

Pugh score: 5 = normal; 6 or 7 = mild (A); 8 or 9 = moderate (B); > 9 = severe (C). Alb = albumin.

X. PHARMACODYNAMICS Patient Case 12. Which one of the following is the most likely reason that a drug will follow clockwise hysteresis? A. Formation of an active metabolite. B. Delay in equilibrium between the blood and the site of action. C. Tolerance. D. Increased sensitivity with time.

A. Definition: Relationship Between Drug Concentrations and the Pharmacologic Response B. Hill Equation

E=

Emax * C EC50 + C

E = pharmacologic response Emax = maximum drug effect EC50 = concentration producing half of the maximum drug effect = shape factor that accommodates the shape of the curve

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Pharmacokinetics: A Refresher

Concentration-response Plot
100 80 60 40 20 0 0 1 2 Concentration/ED50 3 4

Percent of Maximal Response

0.5 1 2 5

Figure 5. Concentration Response Plot

C. Hysteresis Loops Definition: Concentrations late after a dose produce an effect different from that produced by the same concentration soon after the dose.

Effect

Causes: 1. Increased sensitivity 2. Formation of an active metabolite 3. Delay in equilibrium between plasma concentrations and the concentration at the site of action 4. Example: Digoxin

Concentration
Figure 6. Counterclockwise Hysteresis

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Pharmacokinetics: A Refresher

Effect

Causes: 1. Tolerance 2. Formation of an inhibitory metabolite 3. Equilibrium reached faster between arterial blood and site of action vs. venous blood and site of action 4. Examples: Pseudoephedrine, cocaine

Concentration
Figure 7. Clockwise Hysteresis

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Patient Cases 13. P.L., a 45-year-old man with chronic renal failure, is receiving phenytoin 400 mg/day for a history of tonicclonic seizures. His phenytoin concentration today is 13.6 mg/L, and his Alb concentration is 4.2 g/dL. Based on his current concentration, which one of the following choices should be recommended with his dose? A. B. C. D. Make no changes to his drug regimen. Keep the total daily dose the same, but change the regimen to 200 mg 2 times/day. Increase the dose for better seizure control. Decrease the dose to prevent toxicity.

14. N.R. is a 63-year-old man with renal insufficiency who comes to the emergency department in atrial fibrillation with a ventricular rate of 120 beats/minute. Because of his history of ventricular dysfunction, it is decided to initiate him on digoxin for rate control. Which one of the following is correct regarding dosing in this patient? A. B. C. D. The loading dose should remain the same, but the maintenance dose needs to be decreased. The loading dose needs to be decreased, and the maintenance dose should remain the same. Neither the loading dose nor the maintenance dose needs to be adjusted. Both the loading dose and the maintenance dose need to be decreased.

15. P.P. is a 34-year-old man with a history of cerebral palsy and chronic urinary tract infections. He is admitted to the hospital with a Pseudomonas urinary tract infection that is resistant to all antibiotics but aminoglycosides. He is initiated on once-daily tobramycin at 400 mg/day intravenously. Which one of the following statements best describes this high-dose, extended-interval aminoglycoside regimen? A. B. C. D. It takes advantage of the concentration-dependent killing of aminoglycoside. It is more efficacious than standard aminoglycoside dosing. It does not require monitoring of aminoglycoside concentrations. It will not cause nephrotoxicity.

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Pharmacokinetics: A Refresher

Table 9. Specific Drugs Drug Therapeutic Range Sampling Issues Aminoglycosides Cpmax = 410 mg/L Duration of infusion, Amikacin = 20 -30 mg/L timing of first Cpmin < 2 mg/L sample post-infusion Amikacin < 10 mg/L (generally should be 0.5-1 hour) Vancomycin Cpmin = 10 -15 mg/L Controversial whether (1520 mg/L for certain to obtain peaks infections including or concentrations pneumonia, meningitis, altogether and osteomyelitis Phenytoin 10 -20 mg/L In general, obtain Free: 1-2 mg/L trough concentrations

Comments Be familiar with Sawchuk-Zaske method and high-dose, extended-interval dosing

Be familiar with changes in trough concentration recommendations

Percent free increases with renal failure and hypoalbuminemia equations to correct: Change in albumin: Cp Cp = Alb (0.9* ) + 0.1 4.4 Renal failure: Cp = Cp 0.5

Carbamazepine Phenobarbital Valproic acid Digoxin

4-12 mg/L 15- 40 mg/L 50100 mg/L 0.8-2.0 mcg/L

Cyclosporine Lithium Theophylline

100 -250 mcg/L 0.3-1.3 mmol/L 10 -20 mg/L

Prolonged distribution period necessitates sampling > 6 -12 hours postdose Whole blood samples Many drug interactions Prolonged distribution necessitates sampling 12 hours postdose Treat as continuous infusion with sustained-release dosage forms

Renal failure with change in albumin: Cp Cp = (0.48* 0.9* Alb ) + 0.1 4.4 Induces liver enzymes; susceptible to metabolic drug interactions Autoinduction; active metabolite 10,11 epoxide Enzyme inducer Saturable protein binding; percent free increases with renal failure and hypoalbuminemia Vd decreases in renal disease; susceptible to drug interactions

Cp = concentration of drug in plasma.

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Pharmacokinetics: A Refresher

Table 10. CYP Drug Interactions


Gene Designation CYP1A2
Substrates Acetaminophen Amitriptyline Caffeine Clomipramine Clozapine Estradiol Fluvoxamine Haloperidol Imipramine Mirtazapine Olanzapine Riluzole Ropinirole R-warfarin Tacrine Theophylline Zileuton Zolmitriptan

CYP2C9/10
Amitriptyline Carvedilol (levo) Celecoxib Diclofenac Fluoxetine Fluvastatin Ibuprofen Indomethacin Irbesartan Losartan Phenytoin Piroxicam Rosuvastatin S -warfarin Tamoxifen Tolbutamide Valproic acid Zafirlukast

CYP2C19
Amitriptyline Cilostazol Citalopram Clomipramine Diazepam N-desmethyl Diazepam Imipramine Lansoprazole Naproxen Nelfinavir Omeprazole Pantoprazole Phenobarbital Phenytoin Propranolol Rabeprazole (minor) Valproic acid

CYP2D6
Amitriptyline Aripiprazole Carvedilol (dextro) Clomipramine Clozapine Codeine Debrisoquine Desipramine Dextromethorphan Donepezil Duloxetine Flecainide Fluoxetine (norfluoxetine) Fluvoxamine Haloperidol Hydrocodone Imipramine Metoprolol Mirtazapine Nortriptyline Oxycodone Paroxetine Propafenone Propranolol Risperidone Thioridazine Timolol Tramadol Trazodone Venlafaxine

CYP3A4
Alfentanil Alprazolam Amiodarone Amlodipine Atazanavir Atorvastatin Buspirone Carbamazepine Cilostazol Citalopram Clarithromycin Cyclosporine Dapsone Darunavir Delavirdine Diazepam Diltiazem Donepezil Efavirenz Eplerenone Erlotinib Erythromycin Ethinyl estradiol Felodipine Fentanyl Finasteride Fosamprenavir Gefitinib Gleevec Imatinib Indinavir Irinotecan Itraconazole Ketoconazole Lapatinib Lidocaine Lopinavir Lovastatin Methadone Carbamazepine Efavirenz Nevirapine Oxcarbazepine Phenobarbital Phenytoin Midazolam Mirtazapine Nateglinide Nefazodone Nelfinavir Nevirapine Nifedipine Quetiapine Quinidine Rabeprazole Repaglinide Rifabutin Ritonavir R-warfarin Saquinavir Sertraline Sibutramine Sildenafil Simvastatin Sirolimus Tacrolimus Telithromycin Tertiary amines (amitriptyline, clomipramine, imipramine) Tiagabine Tipranavir Trazodone Triazolam Vardenafil Verapamil Voriconazole Zaleplon Zileuton Ziprasidone Zolpidem Zonisamide Pioglitazone Rifabutin Rifampin Rifapentine St. Johns wort Topiramate Indinavir Itraconazole Ketoconazole Lopinavir Nefazodone Nelfinavir Norfluoxetine Ritonavir Saquinavir Synercid Telithromycin Tipranavir Verapamil Voriconazole

CYP2C8 Rosiglitazone

Induction

Chargrilled meat Cigarettes Nafcillin Omeprazole Rifampin Amiodarone Cimetidine Ciprofloxacin Diltiazem Erythromycin Fluvoxamine Grepafloxacin Mexiletine Mibefradil Norfloxacin Tacrine Ticlopidine

Phenobarbital Phenytoin Rifampin Rifapentine

Carbamazepine Phenobarbital Prednisone Rifampin

Inhibition

Amiodarone Fluconazole Fluoxetine Fluvoxamine Isoniazid Leflunomide (metabolism) Omeprazole Sertraline Sulfamethoxazole Trimethoprim Valproic acid Voriconazole Zafirlukast

Cimetidine Felbamate Fluoxetine Fluvoxamine Ketoconazole Lansoprazole Modafinil Omeprazole Oxcarbazepine Pantoprazole Rabeprazole Ticlopidine Topiramate

Amiodarone Bupropion Celecoxib Chlorpheniramine Cimetidine Citalopram Diphenhydramine Escitalopram Fluoxetine Haloperidol Metoclopramide Paroxetine Propafenone Quinidine Ritonavir Sertraline Terbinafine Thioridazine

Amiodarone Aprepitant Atazanavir Cimetidine Clarithromycin Darunavir Delavirdine Diltiazem Erythromycin Fluconazole (large doses) Fluvoxamine Fosamprenavir Grapefruit juice Imatinib

CYP = cytochrome P450.

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Table 11. PK Terms Term Definition AUC Area under the curve AUCEV Area under the curve following an extravascular dose AUCIV Cmax Cmin Cp0 Css Area under the curve following an intravenous dose Maximum concentration Minimum concentration Concentration at time zero Concentration at stead state Average concentration at steady state Maximum concentration at steady state Dose given extravascularly Dose given intravenously Bioavailability Elimination rate constant Rate of infusion Dosing interval Time of the infusion Time from initiation of the infusion Volume of distribution

Css avg

Css max

DoseEV DoseIV F k R0

t ti Vd

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References 1. Burton ME, Shaw LM, Schentag JJ, eds. Applied Pharmacokinetics & Pharmacodynamics: Principles of Therapeutic Drug Monitoring, 4th ed. Baltimore, MD: Lippincott Williams & Wilkins, 2006. 2. Bauer LA. Clinical pharmacokinetics and pharmacodynamics. In: DiPiro JT, Talbert RL, Yee GC, et al, eds. Pharmacotherapy: A Pathophysiologic Approach, 4th ed. Stamford, CT: Appleton & Lange, 1999:2143. 3. Winter ME. Basic Clinical Pharmacokinetics, 3rd ed. Vancouver: Applied Therapeutics, 1994. 4. Bauer LA. Applied Clinical Pharmacokinetics. New York: McGraw-Hill Medical, 2001. 5. Matheny CJ, Lamb MW, Brouwer KLR, Pollack GM. Pharmacokinetic and pharmacodynamic implications of P-glycoprotein modulation. Pharmacotherapy 2001;21:77896. 6. Nyman HA, Dowling TC, Hudson JQ, Peter WL, Joy MS, Nolin TD. Comparative evaluation of the Cockcroft-Gault equation and the Modification of Diet in Renal Disease (MDRD) study equation for drug dosing: an opinion of the Nephrology Practice and Research Network of the American College of Clinical Pharmacy. Pharmacotherapy 2011;31:113044.

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Answers and Explanations to Patient Cases 1. Answer: C In 6 days (2 t1/2), the concentration will decrease from 35.9 mg/L to about 9 mg/L; now is the time to re-dose. A 1-g dose given on March 24 will increase the concentration in the blood from 12.1 mg/L to 35.9 mg/L (12.1 + 23.8 mg/L). Given that the t1/2 is about 3 days, it will take longer than 1 day to reach a concentration of about 10 mg/L. In 3 days (1 t1/2), the concentration will decrease from 35.9 mg/L to about 18 mg/Lstill too early to re-dose. Re-dosing can be figured because plenty of information exists about how to calculate when to re-dose. 2. Answer: A F = (100 mg * 25 mg/L/hour)/(200 mg * 50 mg/L/hour). 3. Answer: c The elimination rate constant equals (ln 6.5 mg/L ln 5.4 mg/L)/12 hours = 0.015 hour-1. The concentration at the end of the infusion equals 6.5 mg/L/e-(0.015*5) = 7 mg/L. The patients Vd = dose/change in concentration or 160 mg/7 mg/L = 22.9 L. If you desire a change in concentration from 1 mg/L to 9 mg/L (or 8 mg/L), then dose = 22.9 L * 8 mg/L = 183.2 mg. Therefore, a dose of 180 mg is appropriate. 4. Answer: D P-glycoprotein is an efflux pump that pumps drugs back into the gastrointestinal lumen. P-glycoprotein is not a plasma protein, and it does not transfer drugs through the gastrointestinal mucosa; rather, it pumps drugs back into the gastrointestinal lumen. In addition, P-glycoprotein acts in concert with CYP3A4 to diminish oral absorption. 5. Answer: C Azithromycin does not inhibit CYP3A4. Erythromycin and clarithromycin are potent inhibitors of CYP3A4 and would be expected to increase cyclosporine concentrations. Cytochrome P450 inhibition is not a drug class effect. 6. Answer: B By definition, clearance becomes nonlinear once the concentration exceeds the K m; therefore, the concentrations will more than double. Phenytoin is not a significant autoinducer. Although phenytoin absorption decreases as the dose is increased, it is not clinically significant until a single dose exceeds 400 mg. 7. Answer: C The correct answer, because of redistribution, is to wait a few hours to obtain the concentration because it will increase significantly within the first few hours after hemodialysis. Waiting a full 24 hours is not necessary. 8. Answer: D The correct answer is that the assay will be able to distinguish the drug from like products but will not be able to detect extremely low concentrations. High specificity means the assay can distinguish the drug from like products, and low sensitivity means the assay cannot detect extremely low concentrations. 9. Answer: C The correct answer is about 60 mL/minute/1.73m 2. This value is calculated using either the Modification of Diet in Renal Disease (study), CKD-Epi (Chronic Kidney Disease Epidemiology Collaboration [formula]), or Cockcroft and Gault equation corrected to 1.73 m 2. The value is much smaller if you use the uncorrected C&G equation because the calculation is in milliliters per minute, not milliliters per minute per 1.73 m 2. 10. Answer: B Both trimethoprim/sulfamethoxazole and cimetidine compete with creatinine for secretion in the kidneys, increasing SCr concentrations. Although angiotensinconverting enzyme inhibitors may transiently increase SCr concentrations, digoxin does not affect renal function. Although furosemide may secondarily affect SCr concentrations, calcium does not affect renal function. Acetaminophen and carvedilol generally will not affect SCr concentrations. 11. Answer: c S.J. has 1 point for not being encephalopathic, 2 points for mild ascites, 2 points for the bilirubin concentration, 2 points for the Alb concentration, and 1 point for the prothrombin time value, for a total of 8 points. Normal patients have a Child-Pugh score of 5, which means no hepatic dysfunction.

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12. Answer: c Tolerance leads to a decrease in effect with time; this is clockwise hysteresis. The formation of an active metabolite, a delay in equilibrium between the blood and site of action, and the increased sensitivity with time would lead to an increase in effect with time; this is counterclockwise hysteresis. 13. Answer: d The dose should be decreased to prevent toxicity. In renal failure, acidic by-products build up in the blood and compete with phenytoin for protein binding. Total concentrations need to be corrected, and this correction leads to a doubling of the concentration. Therefore, the current concentration is too high, and the dose should be decreased. Single doses of 400 mg are fine (doses higher than 400 mg should be divided). 14. Answer: D Both the loading dose and the maintenance dose need to be decreased. In general, loading doses do not need to be altered in renal dysfunction because they are primarily dependent on the Vd. However, the digoxin Vd is decreased in renal dysfunction. Because digoxin is eliminated renally, the maintenance dose needs to be decreased. 15. Answer: a Aminoglycosides show concentration-dependent killing, and a high-dose, extended-interval aminoglycoside dose takes advantage of this characteristic. However, it has not proved to be more efficacious than traditional dosing. Aminoglycoside concentrations still need to be monitored with high-dose, extended-interval therapy. In addition, high-dose, extended-interval aminoglycoside dosing can still cause nephrotoxicity (although the incidence is generally diminished).

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Answers and Explanations to Self-Assessment Questions 1. Answer: B With two concentrations, there are enough data to calculate an elimination rate constant and, therefore, a t1/2. In addition, the Vd can be calculated by back extrapolation to the Cmax and use of appropriate equations (because this was the first dose, and therefore, it is known that the tobramycin concentration was 0 mg/L before the dose was given). 2. Answer: A The t1/2 is about 2 hours. The Cmax is about 5 mg/L, and the Vd is about 20 L. 3. Answer: B Her clearance increased because of the improvement in renal function, which increased her elimination rate constant and decreased her t1/2. The Vd would not be altered by changes in clearance (they are independent). With the diuresis and angiotensin-converting enzyme inhibitor, her Vd probably decreased, but clearance would not be altered by changes in Vd (they are independent). In addition, if her Vd decreased, her t1/2 would decrease, not increase. 4. Answer: C Because the trough is too low, the interval will have to be shortened to increase the concentration. Changes in dose will have the greatest effect on the peak concentration, and changes in interval will have the greatest effect on the trough concentration. 5. Answer: C Her dose needs to be increased, and because she is a smoker, the interval should be every 8 hours. Doubling the total daily dose will adequately increase her concentration without causing toxic reactions. 6. Answer: D Because of the patients renal failure and low Alb, the total concentration needs to be corrected. The patients corrected phenytoin concentration is 14.7 mcg/mL. Therefore, no changes need to be made to the dose. 7. Answer: C Both of these are immunoassays. A brand name for the Abbott fluorescence polarization immunoassay is TDx, which uses a fluorescent label. The term EMIT stands for enzyme multiplied immunoassay technique, which is an immunoassay that uses an enzyme label. 8. Answer: D The digoxin concentration was drawn too close to the 8:00 am dose. The digoxin had not yet had a chance to complete its distribution phase. Once distribution is complete (generally 612 hours after the dose), the concentration will be lower and probably within the therapeutic range. Therefore, there is no need for the digoxin antibody, activated charcoal, or lowering of the dose. 9. Answer: C The correct statistical test is multiple logistic regression. Multiple regression is used to describe the relationship between a dependent variable and two or more independent variables when both the dependent and independent variables are numeric. Analysis of variance is used to describe the relationship between a dependent variable and two or more independent variables when the dependent variable is numeric and the independent variables are nominal. Likewise, analysis of covariance is used to describe the relationship between a dependent variable and two or more independent variables when the dependent variable is numeric and the independent variables are nominal with confounding factors. Spearman rank correlation is a nonparametric test used to describe the relationship between one dependent and one independent variable when the data are ordinal or numeric and not normally distributed. 10. Answer: B Assessing adherence and increasing her dose, because the concentration is below the therapeutic range, is the correct answer. The valproic acid therapeutic range is 50100 mg/L, and she is well below this concentration. Although some patients are controlled at lower concentrations, this concentration is most likely too low. She definitely does not need a decrease in dose. Although total valproic acid concentrations are affected by changes in Alb, N.T.s Alb is normal, and obtaining a free concentration is unnecessary.

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Pharmacokinetics: A Refresher

ACCP Updates in Therapeutics 2012: The Pharmacotherapy Preparatory Review and Recertification Course 2-122