Clinical Pharmacokinetics University of Nizwa College of Pharmacy and Nursing School of Pharmacy Clinical Pharmacokinetics PHCY 350 Lecture-11 Drug Dosing in Special Populations-Renal Disease Dr. Sabin Thomas, M. Pharm. Ph. D. Assistant Professor in Pharmacy Practice School of Pharmacy University of Nizwa

Course Outline Upon completion of this lecture the students will be able to describe the process of drug elimination through kidneys, estimate kidney functions obese and non-obese patients based on the creatinine clearance evaluate drug dosing in individual patients.

Renal or hepatic disease will decrease the elimination or metabolism of the majority drugs and change the clearance of the agent. Most water-soluble drugs are eliminated unchanged to some extent by the kidney. In addition to this, drug metabolites that were made more water soluble via oxidation or conjugation are typically removed by renal elimination. 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 (Glomerular filtration). 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.

fB is the free fraction of drug in the blood, The equation that describes these various routes of renal elimination is: Where, fB is the free fraction of drug in the blood, GFR is glomerular filtration rate, RBF is renal blood flow, Cl′sec is the intrinsic clearance for tubular secretion of unbound drug, FR is the fraction reabsorbed.

Kidney development is complete and renal function stabilizes 3–6 months after birth. Kidney function, as measured by glomerular filtration rate (GFR), 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 GFR is ~50–60 mL/min. The expected GFR 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.

In patients with renal disease, there is a functional loss of nephrons. Patients with acute renal failure 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.

Importance Renal impairment has been estimated to account for one-third of the prescribing errors resulting from inattention to patient pathophysiology. Appropriate dose adjustments often are not made for patients with impaired renal function. Those groups at risk for developing renal impairment include individuals with diabetes, elderly people, those with hypertension, certain ethnic groups and individuals with atherosclerotic disease elsewhere, autoimmune and genetic diseases, or a family history of renal disease. This will ensure the effectiveness of medication, avoid or minimize further kidney damage, and prevent drug nephrotoxicity.

DIAGNOSIS OF RENAL INSUFFICIENCY All patients who are at risk for renal insufficiency should have their renal function assessed as part of their periodic health examination Serum creatinine should be tested, recognizing that measuring serum creatinine alone will fail to diagnose abnormal function in 35% of people aged 40–49 years and 92% of people more than 70 years old A more accurate reflection of renal function is creatinine clearance

STEPWISE GUIDE TO ADJUST DRUG DOSAGE FOR PATIENTS WITH RENAL INSUFFICIENCY Step 1:Take history and perform physical examination. Measurement of height & weight Blood pressure and heart rate with orthostatic changes Jugular venous pulse Edema Ascites Lung crackles Search for signs of chronic liver disease Step 2: Determine the degree of renal insufficiency Measure serum creatinine Order 24-hour urine collection or calculate creatinine clearance

Step 3: Review the medication list Ensure that all drugs are still required and that new medications have specific indications Evaluate for potential drug interactions Step 4: Choose less nephrotoxic drugs If the use of nephrotoxic drugs cannot be avoided without patient morbidity or mortality, then therapeutic drug monitoring or monitoring of renal function is mandatory Step 5: Select loading doses These are usually the same for patients with both normal and abnormal renal functions

Step 6: Select a maintenance regimen Either reduce the dose of the drug and maintain the usual dosing interval or maintain the drug dose and extend the interval Titrate the dose of the drug to patient effect, if applicable (For example, antihypertensives are dosed based upon blood pressure control, whereas antimicrobials are not adjusted according to response). Step 7: Monitor drug levels Monitor drug levels if monitoring is available to guide further therapy

RANGES OF NORMAL AND DECREASED CREATININE CLEARANCE (SI UNITS) Step 8: Reassess Reassess the patient to evaluate drug effectiveness and the need for ongoing therapy If nephrotoxic drugs are used, check the patient's serum creatinine and creatinine clearance again RANGES OF NORMAL AND DECREASED CREATININE CLEARANCE (SI UNITS) Category Value Men (Normal) 95–145 mL/min (1.58–2.42 mL/s) Women (Normal) 75–115 mL/min (1.25–1.92 mL/s) Mild renal insufficiency* 50–70 mL/min (0.83–1.17 mL/s) Moderate renal insufficiency* 25–50 mL/min (0.42–0.83 mL/s) Severe renal insufficiency* < 25 mL/min (< 0.42 mL/s) As GFR increases clearance of drug increases. GFR is zero, clearance is zero.

MEASUREMENT AND ESTIMATION OF CREATININE CLEARANCE… Method recommended by the Food and Drug Administration (FDA) to estimate renal function for drug dosing is to measure or estimate creatinine clearance (CrCl). Creatinine is a by-product of muscle metabolism that is primarily eliminated by glomerular filtration. Because of this property, it (CrCl) is used as a surrogate (substitute) measurement of glomerular filtration rate (GFR). Since creatinine is also eliminated by other routes, CrCl does not equal GFR, so the two parameters are not interchangeable.

CrCl (mL/min) = (UCr ⋅ Vurine) / (SCr ⋅ T) where 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 (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 T is the time in minutes of the urine collection As creatinine renal secretion exhibits diurnal variation (throughout the day), most nephrologists use a 24-hour urine collection period for the determination of creatinine clearance. However, for the purpose of drug dosing, collection periods of 8–12 hours have been sufficient in emergent situations

CrClest = [(140 − age) BW]/ (72 ⋅ SCr) For females: 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 SCr is serum creatinine in mg/dL

[IBW males (in kg) = 50 + 2.3(Ht − 60) or 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] 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. 17

Some patients have decreased muscle mass due to disease states and conditions that effect muscle or prevent exercise, viz., Spinal cord injury Cancer patients with muscle wasting HIV-infected patients Cachectic patients Patients with poor nutrition are examples of situations where muscle mass may be very small resulting in low creatinine production In these cases, serum creatinine concentrations are low because of the low creatinine production rate and not due to high renal clearance of creatinine In these cases, if serum creatinine values are <1.0 mg/dL for a patient an arbitrary value of 1 mg/dL be used in the Cockcroft-Gault formula to estimate creatinine clearance 18

MEASUREMENT AND ESTIMATION OF CREATININE CLEARANCE… If patients are not within 30% of their ideal body weight, other methods to estimate creatinine clearance should be used 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 19

For male: (137 – Age)[(0.285.Wt)+(12.1.Ht2)] CrCl est = (51. SCr) For female: (146 – Age)[(0.287.Wt)+(9.74.Ht2)] (60. SCr) where age is in years Wt is weight in kg Ht is height in m SCr is serum creatinine in mg/dL 20

CrClest (in mL/min / 1.73 m2) = (0.45 ⋅ Ht) / SCr Age 1–20 years 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 SCr is in mg/dL Note that for these formulas, estimated creatinine clearance is normalized to1.73 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 21

Generally, we should consider Estimation of Drug Dosing and Pharmacokinetic Parameters using Creatinine Clearance… Generally, we should consider a modest decrease in drug doses when creatinine clearance is <50−60 mL/min a moderate decrease in drug doses when creatinine clearance is <25−30 mL/min a substantial decrease in drug doses when creatinine clearance is ≤15 mL/min In order to modify doses for patients with renal impairment, It is possible to decrease the drug dose and retain the usual dosage interval. Retain the usual dose and increase the dosage interval, or simultaneously decrease the dosage and prolong the dosage interval 22