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Variability: Kidney Disease

VCU School of Pharmacy PCEU 606 - Applied Pharmacokinetics. Variability: Kidney Disease. Thomas J. Comstock, Pharm.D. Associate Professor Department of Pharmacy and Pharmaceutics School of Pharmacy Virginia Commonwealth University. Learning Objectives.

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Variability: Kidney Disease

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  1. VCU School of Pharmacy PCEU 606 - Applied Pharmacokinetics Variability: Kidney Disease Thomas J. Comstock, Pharm.D. Associate Professor Department of Pharmacy and Pharmaceutics School of Pharmacy Virginia Commonwealth University

  2. Learning Objectives • Understand the role of the kidneys in drug elimination. • Be able to describe tests for kidney function and use the the Cockcroft-Gault method to assess kidney function; understand its limitations. • State the effects of kidney disease on drug absorption, distribution, metabolism, and excretion. • Apply the Dettli method for dosage regimen adjustment in patients with renal dysfunction.

  3. Kidney Function • Endocrine • Metabolic • Excretory • Filtration • Secretion • Reabsorption

  4. Bricker's Intact Nephron Hypothesis Kidney function is best related to its overall excretory capacity, whereby kidney function is the net result of a reduced number of appropriately functioning nephrons

  5. Kidney Function • Cardiac output (CO) • 6 L/min • Renal blood flow (RBF) 20% of CO • 1.2 L/min • Renal plasma flow (RPF) RBF x (1-Hct) • 650 mL/min • Filtration fraction • 20% • Glomerular filtration rate (GFR) RPF x FF; • 125 mL/min

  6. Measurement of GFR CLr = Ae/(AUC0-t) = GFR where: CLr = renal clearance Ae = amount excreted unchanged in the urine AUC0-t = Area under the plasma c vs t curve from 0-t t = time interval for urine collection GFR = glomerular filtration rate CLr = Ae/(Css x t) where: Css = steady-state plasma concentration

  7. Measurement of GFR • Inulin • Iothalamate • Iohexol • Labeled markers • 99mTc-DTPA 125I-Iothalamate • Creatinine

  8. Cockcroft-Gault CLcr Estimation Cockcroft DW, Gault MH. Nephron 1976;16:31-41

  9. Cockcroft-Gault CLcr Derivation

  10. Normalized Cockcroft-Gault

  11. Kidney Function Glomerular Filtration Inulin / Iothalamate / Isotope Clearance Creatinine Clearance (measured) Creatinine Clearance (estimated)

  12. Kidney Disease Effects on Pharmacokinetics • Absorption • Distribution • Metabolism • Excretion • Dialysis

  13. Absorption • Limited data • Drug interactions • Ca-containing PO4 binders and digoxin, fluoroquinolones, tetracycline • Altered first-pass metabolism • propoxyphene, propranolol, Ca-antagonists • Delayed gastric emptying •  Tmax,  Cmax (no change in AUC)

  14. Distribution • Altered acid-base balance • pKa~pH may show change in fraction ionized (e.g. salicylate:  Vd with metabolic acidosis • Altered physiologic volume (e.g. fluid overload) • Altered protein binding (plasma and tissue) • displacement by uremic toxins • altered albumin conformation  altered binding parameters • hypoalbuminemia

  15. Phenytoin: Altered Distribution • Therapeutic total plasma concentration: 10-20 mg/L; fup = 0.10  therapeutic unbound range: 1-2 mg/L Condition fup Total Unbound (mg/L) (mg/L) Normal 0.10 10-20 1-2 Uremic 0.20 5-10 1-2

  16. V (L) CLcr (mL/min) Digoxin: Altered Distribution •  tissue binding • V(normal) = 468 L • V(15mL/min) = 327 L

  17. Metabolism • Kidneys active in drug metabolism, yet overall contribution is small • Renal failure may alter hepatic drug metabolism •  first-pass metabolism for  E drugs • variable effect on Clint • Active metabolites may accumulate • Meperidine  normeperidine • Procainamide N-acetyl procainamide

  18. CLdrug CLcr (mL/min/1.73m2) Excretion • Renal elimination by excretion is considered to be proportional to filtration. • CL = CLr + CLnr; y=mx + b • 3 Drug types • A: Renal • B: Non-renal • C: Renal + Nonrenal • Dettli Relationship B C A

  19. Excretion CL = CLr + CLnr CL* = (CLr x RF) + CLnr where: CL* = CL for a patient with reduced kidney function; RF = Fraction of normal renal function Simplify terms: CLr = CL x fe; CLnr = CL x (1-fe) where fe = fraction of drug eliminated unchanged in the urine, with normal kidney function CL* = (CL x fe x RF) + CL(1-fe)

  20. Excretion Divide by CL: Fraction of normal drug clearance

  21. Excretion • Same approach is used for k, since assumption is that V is constant and not affected by renal function. • k* = (k x fe x RF) + k(1-fe)

  22. Dosage Regimen Design Normal Conditions Renal Impairment

  23. Dosage Regimen Design Since Cavg,ss = C*avg,ss and F, V considered constant:

  24. Dosage Regimen Design For antibiotics, generally adjust ; for other drugs, adjust D and/or to develop convenient regimen

  25. Assumptions of the Dettli Method • No change in F • No change in distribution • No change in protein binding • Direct linear relationship between drug elimination nad renal function • Metabolites are inactive and non-toxic • Normal hepatic function • Normal cardiac function • No change in pharmacodynamics

  26. Dosage Regimen Design - Example • Cimetidine: • fe 0.77 • t1/2 2.1 hrs • normal regimen 300 mg q 6 hrs. PO • Patient: • 56 year-old male • weight 60 kg • Scr 1.4 mg/dL

  27. Dosage Regimen Design - Example

  28. Renal Insufficiency - ExampleGabapentin Blum RA et al. CPT 1994;56:154-9

  29. Renal Insufficiency - ExampleGabapentin:  = 0.00073 Clcr + 0.011 (r=0.85) Blum RA et al. CPT 1994;56:154-9

  30. Renal Insufficiency - ExampleGabapentin: CL/F = 1.61 Clcr +3.57 (r=0.90) Blum RA et al. CPT 1994;56:154-9

  31. Renal Insufficiency - ExampleCefatrizine: CL/F = 2.69 Clcr + 0.69 (r=0.80) Couet W et al. Int J Clin Pharmacol Ther Tox 1991;29:213-17

  32. Renal Insufficiency - ExampleTeicoplanin: CL = 0.0651 Clcr + 4.3975 (r2=0.938) Lam YWF et al. CPT 1990;47:655-61

  33. Renal Insufficiency - ExampleCefepime: CL = 0.96 Clcr + 10.92 (r=0.95) Barbhaiya RH et al. CPT 1990;48:268-76

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