Pharmacokinetics Refresher PDF

Pharmacokinetics: A Refresher Patient Case 7. A drug assay is touted as having high specificity but low sensitivity. Which statement best describes what this means? A. The assay cannot distinguish the drug from like products but cannot detect extremely low concentrations. B. The assay cannot disti...

Pharmacokinetics: A Refresher Patient Case 7. A drug assay is touted as having high specificity but low sensitivity. Which statement best describes what this means? A. The assay cannot distinguish the drug from like products but cannot detect extremely low concentrations. B. The assay cannot distinguish the drug from like products and cannot detect extremely low concentrations. C. The assay can distinguish the drug from like products and can detect extremely low concentrations. D. The assay can distinguish the drug from like products but cannot detect extremely low concentrations. C. Assay Terminology 1. Precision (reproducibility): Closeness of agreement between 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) SD CV = –––––– Mean 2. Accuracy: Closeness with which a measurement reflects the true value of an object • Correlation coefficient: Strength of the relationship between two variables 3. Predictive performance (measure of accuracy): Precision, expressed as the root mean squared error (RMSE) –––– 1 N MSE = –– ∑ pei2 RMSE = √ mse N i =1 Bias: a.k.a. mean prediction error (ME) 1 N ME = –– ∑ 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 D. Assay Methods 1. Immunoassays a. Radioimmunoassay i. Advantages: Extremely sensitive (picogram range) ii. Disadvantages: Radioimmunoassay kits have limited shelf life because of the short half-life of labels, radioactive waste, and cross-reactivity. • Clinical use for assaying digoxin and cyclosporine b. Enzyme immunoassay, e.g., enzyme multiplied immunoassay technique i. Advantages: Simple, automated, highly sensitive, inexpensive and stable reagents, inexpensive and widely available equipment, no radiation hazards ii. Disadvantages: Measuring enzyme activity more complex than radioisotopes, enzyme activity may be affected by plasma constituents, less sensitive than radioimmunoassays ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-93 Pharmacokinetics: A Refresher c.  luorescence immunoassay: TDx (e.g., fluorescence polarization immunoassay): Most common F therapeutic drug monitoring assay i. Advantages: Simple, automated, highly sensitive, inexpensive and stable reagents, inexpensive and widely available equipment, no radiation hazards ii. Disadvantages: Background interference attributable to endogenous serum fluorescence 2. Assays used primarily in pharmacokinetic research studies a. High-pressure liquid chromatography b. Gas chromatography–mass spectrometry and liquid chromatography–mass spectrometry c. Flame photometry d. 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. W hen patient-specific data are limited, there is greater influence from population parameters; when patient-specific data are extensive, there is less influence. c. With a small amount of individual data, Bayesian forecasting generally yields more precise results. Patient Cases 8. K.M., an 80-year-old white woman (52 kg, 64 inches), is admitted to the hospital for pyelonephritis with sepsis. She has a history of myocardial infarction, heart failure with reduced ejection fraction, hypertension, osteoporosis, rheumatoid arthritis, and cerebrovascular accident. On admission, her BUN is 25 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 (240 mg of the trimethoprim component) intravenously every 12 hours, lisinopril 10 mg daily by mouth, digoxin 0.125 mg daily by mouth, furosemide 40 mg daily by mouth, cimetidine 400 mg twice daily by mouth, acetaminophen 650 mg every 6 hours by mouth, calcium carbonate 500 mg three times daily by mouth, and carvedilol 6.25 mg twice daily by mouth. Which is the best assessment of K.M.’s renal function? A. Her SCr is in the normal range, and no dosage adjustments are necessary. B. Because of her age, K.M. will have some degree of renal dysfunction, and dosages may need to be adjusted. C. Because of the pyelonephritis, K.M. will have renal dysfunction, and dosages may need to be adjusted. D. Her SCr is in the normal range but her BUN is elevated, so dosages may need to be adjusted. 9. Which of K.M.’s current medications are most likely to alter her SCr concentrations? A. Lisinopril and digoxin. B. Trimethoprim/sulfamethoxazole and cimetidine. C. Furosemide and calcium carbonate. D. Acetaminophen and carvedilol. ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-94 Pharmacokinetics: A Refresher VIII. PHARMACOKINETICS IN RENAL DISEASE A. Estimation of Kidney Function Through Glomerular Filtration Rate (GFR) and Creatinine Clearance (CrCl) 1. Creatinine production and elimination a. Creatine is produced in the liver. b. Creatinine is the product of creatine metabolism in skeletal muscle, formed at a constant rate for any one person. c. Creatinine is filtered at the glomerulus, where it undergoes limited secretion. d. CrCl is useful in approximating GFR because: i. At normal concentrations of creatinine, secretion is low. ii. The creatinine assay picks up a noncreatinine 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: volume of urine (mL)/1440 minutes × urine creatinine concentration (mg/dL) CrCl (mL/minute/1.73 m2) = –––––––––––––––––––––––––––––––––––––––––––––––––– serum creatinine concentration (mg/dL) • Normal CrCl Healthy young men = 125 mL/minute/1.73 m2 Healthy young women = 115 mL/minute/1.73 m2 • After age 30, 1% of GFR is lost per year. 3. CrCl estimation to estimate GFR a. Factors affecting SCr concentrations i. Sex ii. Age iii. Weight and muscle mass iv. Renal function. Caveats: CrCl estimations worsen as renal function worsens (usually an overestimation). b. Jeliffe 98 – 0.8 (age – 20) CrCl (mL/minute/1.73 m2) = –––––––––––––––– SCr Women: Use 90% of the above equation. • Limitations SCr concentration must be stable. Adults 20–80 years of age (equation only applies to this age group) Controversy: Rounding up SCr in patients with low concentrations (less than 0.7–1 mg/dL) c. Cockcroft-Gault (140 - Age) * (weight) CrCl(mL/min) = –––––––––––––––––– 72 * Scr Women: Use 85% of the above equation. • For “weight”: Use actual body weight (ABW) in patients with body mass index (BMI) less than 18.5 kg/m2, ideal body weight (IBW) in patients with BMI 18.5–25 kg/m2, and IBW plus 40% of (ABW – IBW) in patients with BMI greater than 25 kg/m 2. 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 ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-95 Pharmacokinetics: A Refresher • R  ecommended when making drug dosage adjustments in patients with renal dysfunction, because package insert recommendations generally use this formula to estimate creatinine clearance, and the use of the Modification of Diet in Renal Disease (MDRD) and Chronic Kidney Disease Epidemiology Collaboration (CKD-Epi) equations to make dosing adjustments has not been validated. • Limitations SCr concentration must be stable. Developed for adults only Not corrected for creatinine standardization (results in lower estimations) Not developed in patients with obesity (see weight recommendations above) d. Salazar-Corcoran CrCl male (mL/min/1.73 m2) = (137 − age) * [(0.285 * weight) + (12.1 * height2)] –––––––––––––––––––––––––––––––––––––– 51 * SCr CrCl female (mL/min/1.73 m2) = (146 − age) * [(0.287 * weight) + (9.74 * height2)] –––––––––––––––––––––––––––––––––––––– 60 * SCr e. • For “weight”: Use actual body weight in kg • For “height”: Use meters • Used for patients with obesity. No better than using Cockcroft-Gault with appropriate weight adjustments (see above) MDRD study equation Full equation  GFR (mL/minute/1.73 m 2) = 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/1.73 m 2) = 161.5 * (Scr)-1.154 * (age in years)-0.203 * 1.212 (if patient is African American) * 0.742 (if patient is a woman) f. i. These equations directly estimate GFR (not CrCl) and were developed using standardized creatinine concentrations to stage kidney function. 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/1.73 m 2 iv. If used for drug dosing, convert value from milliliters per minute per 1.73 m 2 to milliliters per minute. v. If used for drug dosing and significantly different from Cockcroft-Gault, use clinical judgment and optimize risk versus benefit. CKD-Epi equation (Table 10) i. These equations directly estimate GFR (not CrCl). ii. These equations are more accurate than MDRD at higher GFRs (i.e., greater than 60 mL/ minute/1.73 m2). CKD-Epi is recommended by KDIGO as the preferred equation for chronic kidney disease staging. ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-96 Pharmacokinetics: A Refresher Table 10. Chronic Kidney Disease Epidemiology Collaboration Equation Race and Sex Female Male Female Male Serum Creatinine (mg/dL) Equation African American < 0.7 166 * (Scr/0.7)-0.329 * (0.993)Age > 0.7 166 * (Scr/0.7)-1.209 * (0.993)Age < 0.9 163 * (Scr/0.9)-0.411 * (0.993)Age > 0.9 163 * (Scr/0.9)-0.411 * (0.993)Age White or other <0.7 GFR =144 * (Scr/0.7)-0.329 * (0.993)Age > 0.7 GFR = 144 * (Scr/0.7)-1.209 * (0.993)Age < 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. g. Pediatric formulas (Table 11). Do not round up low SCr values in pediatric patients. Schwartz: K * ht (cm) GFR (mL/minute/1.73 m2) = –––––––––– SCr Table 11. Schwartz Equation Constants Age Low birth weight ≤ 1 year Full term ≤ 1 year 1–13 years 13- to 18-year-old adolescent female 13- to 18-year-old adolescent male K 0.33 0.45 0.55 0.55 0.7 Note: K = 0.413 for 1–13 years old and 13- to 18-year-old adolescent females when using standardized creatinine concentrations (other K values have not been updated); this is known as the bedside Chronic Kidney Disease in Children (CKiD) equation. Counahan-Barratt: 0.43 * ht (cm) GFR (mL/minute/1.73 m2) = –––––––––––– SCr 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 and 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-Barré 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) ix. Hydration status (dehydration vs. fluid overload) ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-97 Pharmacokinetics: A Refresher c. Diet i. High-meat protein diets (↑ creatinine ingestion) ii. Vegetarians (↓ creatinine ingestion) iii. Protein calorie malnutrition (↓ creatinine ingestion) d. Drugs and endogenous substances i. Laboratory interaction: Kinetic alkaline picrate method (a) Noncreatinine chromogens: In blood but not in urine (b) Cephalosporins (especially cefoxitin): Chromogenic, causing false elevations that are much greater in urine than in blood (c)  Acetoacetate (elevated in fasting patients, patients with diabetic ketoacidosis): Chromogenic, causing false elevations ii. Pharmacokinetic interaction: Drugs compete with creatinine for renal secretion (causing false elevations), cobicistat, trimethoprim, cimetidine, fibric acid derivatives (other than gemfibrozil), and dronedarone. B. Drug Dosing in Renal Disease 1. Loading dose a. In general, no alteration is necessary, but it should be given to hasten the achievement of therapeutic drug concentrations. b. Alterations in loading dose must occur if the Vd is altered secondary to renal dysfunction. Example: Decrease digoxin loading doses in renal disease because of a decreased Vd. 2. Maintenance dosage: Alterations should be made in either the dosage 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 dosage i. Use when the goal is to maintain a steady therapeutic concentration. ii. More costly c. Changing the dosage and the dosing interval i. Often necessary for substantial dosage adjustment with limited-dosage forms ii. Often necessary 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 dosage. d. Augmented renal clearance i. Increased creatinine clearance in critically ill patients, resulting in greater elimination of renally eliminated drugs ii. Most common in patients with severe neurologic injury, sepsis, trauma, or burns iii. Associated with subtherapeutic concentrations of antibiotics, especially β-lactams and vancomycin Patient Case 10. S.J. is a 55-year-old man with hepatic dysfunction and an anaerobic infection caused by Prevotella spp. He has a small amount of ascites but is not encephalopathic. He is initiated on metronidazole, and the package insert states that dosages should be decreased by 50% in patients with a Child-Pugh score greater than 9. If he has the following hepatic laboratory values, which best estimates his Child-Pugh score? ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-98 Pharmacokinetics: A Refresher Patient Case (Cont’d) 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, γ-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 dosages in hepatic disease. 2. Low–hepatic extraction ratio drugs a. Adjustment of maintenance dosage is necessary only when hepatic disease alters the intrinsic clearance (Clint). b. Alterations in protein binding alone do not require alteration of maintenance dosage, even though total drug concentrations decline. c. Loading doses may require reduction. d. Examples: carbamazepine, diazepam, phenytoin, warfarin 3. High–hepatic extraction ratio drugs a. Intravenous administration i. Usually necessary to decrease maintenance dose rate as hepatic blood flow changes ii. Consider effect of hepatic disease on protein binding as it alters free concentrations. b. Oral administration: Similar to low–hepatic extraction ratio drugs; necessary to decrease maintenance dose rate when hepatic disease alters Clint c. Examples: haloperidol, morphine, metoprolol, propranolol, verapamil B. Rules for Dosing in Hepatic Disease 1. Hepatic elimination of high–extraction ratio drugs is more consistently affected by liver disease than hepatic elimination of low–extraction ratio drugs. 2. The clearance of drugs that are exclusively conjugated is not substantially altered in liver disease. 3. Adjustments for some drugs based on Child-Pugh scores (Table 12). Table 12. Child-Pugh Classification for Liver Disease Encephalopathy Ascites Bilirubin (mg/dL) Albumin (g/dL) Prothrombin time (seconds over control) or INR (values in brackets) 1 0 0 <2 > 3.5 0–4 [< 1.7] Points 2 1 or 2 + 2–3 2.8–3.5 4–6 [1.7–2.3] 3 3 or 4 ++ >3 < 2.8 >6 [> 2.3] Pugh score: 5 = normal; 6 or 7 = mild (A); 8 or 9 = moderate (B); >9 = severe (C). ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-99 Pharmacokinetics: A Refresher X. PHARMACODYNAMICS Patient Case 11. Which 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 Emax *C y E = –––––––––– EC50y + C y Percent of Maximal Response E = pharmacologic response Emax= maximum drug effect EC50 = concentration producing half of the maximum drug effect γ = Hill coefficient that accommodates the shape of the curve 100 Hill coefficients 80 0.5 1 2 5 60 40 20 0 0 1 2 3 4 Concentration/ED50 Figure 5. Concentration response plot. ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-100 Pharmacokinetics: A Refresher C. H  ysteresis Loops. Definition: Concentrations late after a dose produce an effect different from that produced by the same concentration soon after the dose. Causes: 1. Increased sensitivity 2. Formation of an active metabolite 3. Delay in equilibrium between plasma concentrations and the concentrations at the site of action 4. Example: Digoxin Effect Concentration Figure 6. Counterclockwise hysteresis. Causes: 1. Tolerance 2. Formation of an inhibitory metabolite 3. E  quilibrium reached faster between arterial blood and site of action vs. venous blood and site of action 4. Examples: Pseudoephedrine, cocaine Effect Concentration Figure 7. Clockwise hysteresis. ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-101 Pharmacokinetics: A Refresher XI. THERAPEUTIC DRUG MONITORING (Table 13) Table 13. Therapeutic Drug Monitoring of Specific Drugs Drug Therapeutic Range Aminoglycosides Peak = 4–10 mg/L maximum Duration of infusion, timing of first sample after infusion Amikacin = 20–30 mg/L Trough < 2 mg/L minimum (generally should be ½–1 hour) Amikacin < 10 mg/L Sampling Issues Comments High-dose extended-interval (“once-daily”) aminoglycoside dosing is generally recommended to decrease toxicity and improve efficacy These regimens are just as effective as traditional dosing, and meta-analyses have demonstrated less nephrotoxicity or no difference Trough-only monitoring of vancomycin Bayesian-derived AUC/MIC AUC derived by (1) collecting two ratio of 400–600 concentrations (a near steady-state, is no longer recommended for serious methicillin-resistant Staphylococcus post-distributional Cmax at 1–2 hr post-infusion, and a trough) during aureus infections, and clinical PK the same dosing interval and using services should move to AUC/MIC first-order PK equations to estimate monitoring. If an MIC is not available, the AUC or (2) collecting one or two assume 1 mg/L. Loading doses are concentrations (at least one trough) recommended for ICU patients, those receiving renal replacement therapy, and and using Bayesian software those receiving continuous infusions programs to estimate the AUC 10–20 mg/L In general, obtain trough Percentage free increases with renal failure and hypoalbuminemia Free: 1–2 mg/L concentrations Higher maximum concentrations for high-dose extended-interval dosing Vancomycin Phenytoin/ Fosphenytoin Equations to correct: Changes in albumin: Cp’ Cp = –––––––––––––– Alb (0.9 * ––– ) + 0.1 4.4 Renal failure: Cp’ Cp = –––––– 0.5 Renal failure with change in albumin: Cp’ Cp = –––––––––––––––––––– Alb (0.48 * 0.9 * –––– ) + 0.1 4.4 Carbamazepine 4–12 mg/L Phenobarbital Valproic acid 15–40 mg/L 50–100 mg/L Digoxin 0.8–2 mcg/L Cyclosporine Lithium 100–250 mcg/L 0.3–1.3 mmol/L Theophylline 10–20 mg/L Prolonged distribution period necessitates sampling > 6–12 hours after dose Whole blood samples Prolonged distribution necessitates sampling 12 hours after dose Enzyme inducer; susceptible to metabolic drug interactions Enzyme inducer/autoinduction; active metabolite 10,11 epoxide Enzyme inducer Saturable protein binding; percentage free increases with renal failure and hypoalbuminemia Volume of distribution decreases in renal disease; susceptible to drug interactions Many drug interactions Treat as continuous infusion with sustained-release dosage forms Cp = concentration of drug in plasma; Vd. ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-103