Therapeutic Drug Monitoring Lecture 3 PDF

Therapeutic Drug Monitoring Lecture 3 PK in Special Populations Department of Clinical Pharmacy/fifth stage 1- INTRODUCTION All medications have specific disease states and conditions that change the pharmacokinetics of the drug and warrant dosage modification. However, the dosing of most drugs will...

Therapeutic Drug Monitoring Lecture 3 PK in Special Populations Department of Clinical Pharmacy/fifth stage 1- INTRODUCTION All medications have specific disease states and conditions that change the pharmacokinetics of the drug and warrant dosage modification. However, the dosing of most drugs will be altered by one or more of the important factors discussed in this chapter??. a/ Renal or b/ hepatic disease will decrease the elimination or metabolism of the majority drugs and change the clearance of the agent. c/ Dialysis procedures, conducted using artificial kidneys in patients with renal failure, removes some medications from the body while the pharmacokinetics of other drugs are not changed. d/ Heart failure results in low cardiac output which decreases blood flow to eliminating organs, and the clearance rate of drugs with moderate-to-high extraction ratios are particularly sensitive to alterations in organ blood flow. e/ Obesity adds excessive adipose tissue to the body which may change the way drugs distribute in the body and alter the volume of distribution for the medication. Finally, f/ drug interactions can inhibit or induce drug metabolism, alter drug protein binding, or change blood flow to organs that eliminate or metabolize the drug. 2 2- RENAL DISEASE: The nephron is the functional unit of the kidney that is responsible for waste product removal from the body and also eliminates drug molecules. Unbound drug molecules that are relatively small are filtered at the glomerulus. 1- Glomerular filtration is the primary elimination route for many medications. 2- Drugs can be actively secreted into the urine, and this process usually takes place in the proximal tubules. Tubular secretion is an active process conducted by relatively specific carriers or pumps that move the drug from blood vessels in close proximity to the nephron into the proximal tubule. 3- Additionally, some medications may be reabsorbed from the urine back into the blood by the kidney. Reabsorption is usually a passive process and requires a degree of a/ lipid solubility for the drug molecule. Thus, tubular reabsorption is influenced by the b/ pH of the urine, the c/ pKa of the drug molecule, and the resulting extent of d/ molecular ionization. Compounds that are not ionized in the urine are more lipid soluble, better able to pass through lipid membranes, and more prone to renal tubular reabsorption. The equation that describes these various routes of renal elimination is: 3 2-1 glomerular filtration rate Kidney function, as measured by glomerular filtration rate, ## typically averages ~120–140 mL/min in young, healthy adults between the ages of 18– 22 years. As humans age, there is a gradual decline in glomerular function ## so that by 65 years of age, the average glomerular filtration rate is ~50–60 mL/min. The expected glomerular filtration rate for otherwise healthy, ## normal 80-year-old adults is ~30–40 mL/min. A glomerular filtration rate of 80–120 mL/min is usually considered the normal range by most clinical laboratories. 4 2-2 Renal failure: In patients with renal disease, there is a functional loss of nephrons. Depending on the etiology of the renal disease. ## Patients with acute renal failure due to a sudden decrease in renal blood flow, such as that seen during hypotension, shock, or hypovolemia, or due to nephrotoxic drug therapy such as aminoglycoside antibiotics or vancomycin, often have their kidney function return to its pre-insult level if they survive the underlying causes of their renal dysfunction. ## Patients with chronic renal failure sustain permanent loss of functional nephrons due to irreversible damage and do not recover lost kidney function. 5 Creatinine clearance rates can be measured by collecting urine for a specified period and collecting a blood sample for determination of serum creatinine at the midpoint of the concurrent urine collection time: CrCl (in mL/min) = (UCr ⋅ Vurine) / (SCr ⋅ T) where UCr is the urine creatinine concentration in mg/dL, Vurine is the volume of urine collected in mL, SCr is the serum creatinine collected at the midpoint of the urine collection in mg/dL, and T is the time in minutes of the urine collection. Because creatinine renal secretion exhibits diurnal variation, most nephrologists use a 24-hour urine collection period for the determination of creatinine clearance. For example, a 24-hour urine was collected for a patient with the following results: UCr = 55 mg/dL, Vurine = 1000 mL, SCr = 1.0 mg/dL, T = 24 h × 60 min/h = 1440 min, and CrCl (in mL/min) = (UCr ⋅ Vurine) / (SCr ⋅ T) = (55 mg/dL ⋅ 1000 mL) / (1.0 mg/dL ⋅ 1440 min) = 38 mL/min. 6 The most widely used of these formulas for adults aged 18 years and older is the method suggested by Cockcroft and Gault: for males, CrClest = [(140 − age) BW]/ (72 ⋅ SCr); for females, CrClest = [0.85(140 − age)BW] / (72 ⋅ SCr); where CrClest is estimated creatinine clearance in mL/min, age is in years, BW is body weight in kg, and SCr is serum creatinine in mg/dL. The Cockcroft-Gault method should only be used in patients ≥18 years old, actual weight within 30% of their ideal body weight IBW males (in kg) = 50 + 2.3(Ht − 60) or IBW females (in kg) = 45 + 2.3(Ht − 60), where Ht is height in inches, and stable serum creatinine concentrations. The 0.85 correction factor for females is present because women have smaller muscle mass than men and, therefore, produce less creatinine per day. 7 For example, a 55-year-old, 80-kg, 5-ft 11-in male has a serum creatinine equal to 1.9 mg/dL. The estimated creatinine clearance would be: IBW males = 50 + 2.3 (Ht − 60) = 50 + 2.3(71 − 60) = 75 kg, so the patient is within 30% of his ideal body weight and the Cockcroft-Gault method can be used; CrClest = [(140 − age)BW] / (72 ⋅ SCr) = [(140 − 55 y)80 kg] / (72 ⋅ 1.9 mg/dL) = 50 mL/min. 8 It has been suggested that use of ideal body weight or adjusted body weight (ideal body weight plus 40% of obese weight) instead of actual body weight in the Cockcroft-Gault equation gives an adequate estimate of creatinine clearance for obese individuals. However, a specific method suggested by Salazar and Corcoran for estimating creatinine clearance for obese patients has been shown to be generally superior: where age is in years, Wt is weight in kg, Ht is height in m, and SCr is serum creatinine in mg/dL. 9 Methods to estimate creatinine clearance for children and young adults are also available according to their age: age 0–1 year, CrClest (in mL/min / 1.73 m2) = (0.45 ⋅ Ht) / SCr age 1–20 years, CrClest (in mL/min / 1.73 m2) = (0.55 ⋅ Ht)/SCr where Ht is in cm and SCr is in mg/dL. Note that for these formulas, estimated creatinine clearance is normalized to 1.73 m2 which is the body surface area of an adult male with a height and weight of approximately 5 ft 10 in and 70 kg, respectively. 10 Estimation of Drug Dosing and Pharmacokinetic Parameters Using Creatinine Clearance Serum concentration versus time profile for a patient with normal kidney function receiving a renally eliminated drug at the dose of 300 mg every 6 hours (solid line). In a patient with renal dysfunction, it is possible to give the same dose and prolong the dosage interval (300 mg every 12 hours, dashed line), or a reduced dose at the same dosage interval (150 mg every 6 hours, dotted line). Giving the same dose at a longer dosage interval in the patient with renal disease usually results in a concentration/time profile similar to that seen in a normal patient receiving the normal dose. However, giving a smaller dose and keeping the dosage interval the same usually produces a concentration/time profile with a lower peak steady-state concentration and a higher trough steady-state concentration. Note that since the total daily dose is the same for both renal disease dosage regimens (600 mg/d), the average steady-state concentration is identical for both dosage schemes. The same dosage options are available for liver-metabolized drugs for patients with hepatic dysfunction. 11 HEPATIC DISEASE Most lipid-soluble drugs are metabolized to some degree by the liver. Phase I type reactions, such as oxidation, hydrolysis, and reduction, are often mediated by the cytochrome P-450 enzyme system (CYP) which is bound to the membrane of the endoplasmic reticulum inside hepatocytes. Phase II type reactions, including conjugation to form glucuronides, acetates, or sulfates, may also be mediated in the liver by cytosolic enzymes contained in hepatocytes. Phase I and phase II drug metabolism generally results in metabolites that are more water soluble and prone to elimination by the kidney. Transport proteins, such as P-glycoprotein, actively secrete drug molecules into the bile. 12 There are two major types of liver disease: hepatitis and cirrhosis. Patients with hepatitis experience an inflammation of the liver, and as a result, hepatocytes may experience decreased ability to function or die. Patients with acute hepatitis usually experience mild, transient decreases in drug metabolism that require no or minor changes in drug dosing. If the patient develops chronic hepatitis, it is likely that irreversible hepatocyte damage will be more widespread, and drug dosage changes will be required at some point. In patients with hepatic cirrhosis, there is a permanent loss of functional hepatocytes. 13 Determination of Child-Pugh Scores: The Child-Pugh score consists of five laboratory tests or clinical symptoms. The five areas are: serum albumin, total bilirubin, prothrombin time, ascites, and hepatic encephalopathy. The Child-Pugh score for a patient with normal liver function is 5 while the score for a patient with grossly abnormal serum albumin, total bilirubin, and prothrombin time values in addition to severe ascites and hepatic encephalopathy is 15. 14 A Child-Pugh score equal to 8–9 is grounds for a moderate decrease (~ 25%) in initial daily drug dose for agents that are primarily (≥60%) hepatically metabolized, and a score of 10 or greater indicates that a significant decrease in initial daily dose (~ 50%) is required for drugs that are mostly liver metabolized. 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. For example, the usual dose of a medication that is 95% liver metabolized is 500 mg every 6 hours, and the total daily dose is 2000 mg/d. For a hepatic cirrhosis patient with a Child-Pugh score of 12, an appropriate initial dose would be 50% of the usual dose or 1000 mg/d. The drug could be prescribed to the patient as 250 mg every 6 hours or 500 mg every 12 hours. The patient would be closely monitored for harmacologic and toxic effects due to the medication, and the dose would be modified as needed. 15 16 Implications of Hepatic Disease on Serum Drug Concentration Monitoring and Drug Effects Hepatic drug metabolism is described by the following equation: where LBF is liver blood flow, fB is the fraction of unbound drug in the blood, and Cl′int is intrinsic clearance. ## For drugs with a low hepatic extraction ratio (≤30%), the numeric value of liver blood flow is much greater than the product of unbound fraction of drug in the blood and the intrinsic clearance of the compound (LBF>>fB ⋅ Cl′int), and the sum in the denominator of the hepatic clearance equation is almost equal to liver blood flow [LBF ≈ LBF + (fB ⋅ Cl′int)]. When this substitution is made into the hepatic clearance equation, hepatic clearance is equal to the product of free fraction in the blood and the intrinsic clearance of the drug for a drug with a low hepatic extraction ratio: ## Similarly, for drugs with a high hepatic extraction ratio (≥70%), the numeric value of liver blood flow is much less than the product of unbound fraction of drug in the blood and the intrinsic clearance of the agent (LBF