Effect of Renal Disease on Pharmacokinetics Dr Mohammad Issa Saleh

Introduction Most water-soluble drugs are eliminated unchanged to some extent by the kidney. 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

Introduction Unbound drug molecules that are relatively small are filtered at the glomerulus. Glomerular filtration is the primary elimination route for many medications 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

Introduction 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 lipid solubility for the drug molecule. Thus, tubular reabsorption is influenced by the pH of the urine, the pKa of the drug molecule, and the resulting extent of 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

Effect of Renal Disease on Drug Absorption The bioavailability of most drugs that have been studied in renal failure has not been altered. In chronic renal failure, D-xylose, a marker for small intestinal absorptive function: Absorption was slower (0.555 h-1 vs. 1.03 h-1) Less complete (48.6% vs. 69.4%) Bioavailability decreased for furosemide and pindolol in renal failure

Bioavailability in Renal Disease Unchanged Increased Cimetidine Dextropropoxyphene Ciprofloxacin Erythromycin Codeine Propranolol Digoxin Tacrolimus

Effect of Renal Disease on Drug Distribution Binding of acidic drugs (phenytoin, sulfonamides, warfarin, furosemide) is decreased in uremic patients. Displaced from albumin by organic acids that accumulate in uremia. Higher concentration of free drug may alter interpretation of therapeutic range

Effect of Renal Disease on Drug Distribution Presence of edema and ascites may increase volume of distribution of hydrophilic and highly protein bound drugs In nephrotic syndrome (with extensive loss of plasma proteins) the binding of clofibric acid, the active metabolite of clofibrate, decreases. This results in an increased volume of distribution

Effect of Renal Disease on Drug Distribution Volume of distribution (L/kg) Drug Normal ESRD Increased V Furosemide 0.11 0.18 Gentamicin 0.2 0.29 Phenytoin 0.64 1.4 Trimethoprim 1.36 l.83 Decreased V Digoxin 7.3 4.1 Ethambutol 3.7 1.6

Measurement and Estimation of Creatinine Clearance

Introduction Glomerular filtration rate can be determined by administration of special test compounds such as inulin or 125I-iothalamate; this is sometimes done for patients by nephrologists when precise determination of renal function is needed Glomerular filtration rate (GFR) can be estimated using the modified Modification of Diet in Renal Disease (MDRD) equation: GFR (in mL/min / 1.73 m2) = 186×SCr −1.154×Age−0.203×(0.742, if female)×(1.21, if African-American) For example, the estimated GFR for a 53-year-old African-American male with a SCr = 2.7 mg/dL would be computed as follows: GFR = 186 ⋅ (2.7 mg/dL)−1.154 ⋅ (53 y)−0.203 ⋅ 1.21 = 32 mL/min / 1.73 m2

Introduction However, the method recommended by the Food and Drug Administration (FDA) and others to estimate renal function for the purposes of 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 is used as a surrogate measurement of glomerular filtration rate Since creatinine is also eliminated by other routes, CrCl does not equal GFR, so the two parameters are not interchangeable.

Equations for body surface area (BSA): Reference: Dubois; Arch Internal Med 1916;17:863

Equation for Ideal Body Weight (IBW): Devine; Drug Intell Clin Pharm 1974;8:650

Estimation of GFR using serum creatinine (Scr) Creatinine is endogenous substance derived from muscle metabolism, small & not bound to plasma proteins, maintains a fairly constant level, and predominantly filtered ~85% (~15% TS) with minimal non-renal elimination. Proportional to muscle mass & body weight Normal 24-hour excretion: 20-25 mg/kg IBW (males) and 15-20mg/kg (females) Creatinine production decreases with age: 2mg/kg/24hrs per decade Several equations have been published to predict GFR using creatinine clearance (Clcr)

Estimation of GFR using Cockcroft-Gault Equation Cockroft D.W., Gault M.H. Prediction of creatinine clearance from serum creatinine. Nephron. 1976;16(1):31-41

Estimation of GFR using Cockcroft-Gault Equation Actual body weight (BW) is used in underweight patients (BW < IBW) Ideal body weight (IBW) in patients of normal weight (BW < 1.3*IBW) Adjusted body weight (ABW) is used for overweight, obese, and morbidly obese patients (BW > 1.3*IBW), suggest use Salazar & Corcoran equation Winter MA, Guhr KN, Berg GM. Impact of various body weights and serum creatinine concentrations on the bias and accuracy of the Cockcroft-Gault equation. Pharmacotherapy 2012;32:604-12.

Estimation of GFR using Cockcroft-Gault Equation Elderly: The Cockcroft & Gault equation tends to over-estimate CLCR in the elderly. Therefore, an empiric "correction" commonly employed is to round up the serum creatinine to 1.0 mg/dL in elderly patients. However, most studies have found this to be an inappropriate practice which under-estimates true ClCr. Very low serum creatinine: Use of a very low serum creatinine (0.5 mg/dL or less) in the C&G equation leads to a falsely elevated ClCr. Therefore, many practitioners designate 0.7 mg/dL as the minimum SCr which should be used in the equation. Rising serum creatinine: If the serum creatinine is rising, it is likely not at steady-state. SCr may require one week to stabilize following a decrease in renal function. Conversely, after renal function improves to normal, the shift of SCr to its new steady-state level occurs rapidly, since the new half life is now quite short. Thus, the probability that SCr may not be at steady-state is much greater when SCr is rising, than when it is falling. Jelliffe's multi step method, which corrects for rising SCr, is more accurate than C&G in patients with unstable renal function.

Estimation of GFR in obese patients (>130% X IBW) using Salazar-Corcoran Equation Salazar DE, Corcoran GB. Predicting creatinine clearance and renal drug clearance in obese patients from estimated fat-free body mass. Am J Med. 1988 Jun;84(6):1053-60

Estimation of Clcr in Pediatrics Schwartz GJ et al. J Pediatr. 1984;104:849-54 and Pediatrics. 1976;58:259-63.

Patients with unstable renal function: Jelliffe's multi step If serum creatinine values are not stable, but increasing or decreasing in a patient, the Cockcroft-Gault equation cannot be used to estimate creatinine clearance. In this case, an alternate method must be used which was suggested by Jelliffe and Jelliffe Jelliffe RW, Jelliffe SM. Math Biosci. 14:17-24 (June) 1972

Jelliffe Multi-step method Estimate creatinine Volume of distribution (Vcr) Jelliffe RW, Jelliffe SM. Math Biosci. 14:17-24 (June) 1972

Jelliffe Multi-step method Estimate creatinine production Jelliffe RW, Jelliffe SM. Math Biosci. 14:17-24 (June) 1972

Jelliffe Multi-step method Estimate creatinine clearance (ml/min) where Scr1 is the first serum creatinine and Scr2 is the second serum creatinine both in mg/dL, and Δt is the time that expired between the measurement of Scr1 and Scr2 in days When SCr rises, last SCr observation is used instead of average SCr Jelliffe RW, Jelliffe SM. Math Biosci. 14:17-24 (June) 1972

Jelliffe Multi-step method Estimate creatinine clearance (standardized to BSA, ml/min/1.73m2 ) Jelliffe RW, Jelliffe SM. Math Biosci. 14:17-24 (June) 1972

Estimation of GFR using Jelliffe Multi-step method Actual body weight (BW) is used in underweight patients (BW < IBW) Ideal body weight (IBW) in patients of normal weight (BW < 1.3*IBW) Adjusted body weight (ABW) is used for overweight, obese, and morbidly obese patients (BW > 1.3*IBW)

Estimation of GFR by calculating Clcr from 24-hour urine collection Where: Ucr = urine creatinine concentration (mg/dL); Uvol = total urine volume (ml/24 hrs); SCr = serum creatinine (mg/dL)

Estimation of GFR by calculating Clcr from 24-hour urine collection

Example 1 A creatinine clearance is measured in a 75-year-old Caucasian male patient with multiple myeloma to monitor changes in renal function. The serum creatinine, measured at the midpoint of the 24 hour urine collection, was 2.1 mg/dL. Urine creatinine concentration was 50 mg/dL, and urine volume was 1400 mL. Calculate this patient’s creatinine clearance.