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Source: Matzke GR. Drug Therapy Individualization for Patients with Chronic Kidney Disease. In: DiPiro, JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM. Pharmacotherapy: A Pathophysiologic Approach. 8th edition. http://accesspharmacy.com/content.aspx?aid=7983360 and Dager W, Halilovic J. Acute Kidney Injury. In: DiPiro, JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM. Pharmacotherapy: A Pathophysiologic Approach. 8th edition. http://accesspharmacy.com/content.aspx?aid=7980960. Accessed August 15, 2012.

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  • Chronic kidney disease (CKD) causes changes in disposition of some drugs as result of changes in bioavailability, distribution volume, and metabolic activity.
  • Drug therapy individualization (DTI) may involve:
    • Simple proportional dose adjustment based on creatinine clearance (CLcr) or glomerular filtration rate (GFR)
    • Complex adjustments for drugs extensively metabolized or undergoing dramatic changes in protein binding and distribution volume.
  • Patient response to given drug may differ because of physiologic and biochemical changes associated with CKD.
  • Goals of DTI: design drug regimens to optimize therapeutic outcomes and minimize adverse effects.

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  • Drug absorption
    • Little quantitative information available
    • Bioavailability theoretically affected by:
      • Alterations in gastrointestinal (GI) transit time
      • Gastric pH
      • Edema of GI tract
      • Vomiting and diarrhea
      • Concomitant drug therapy, especially antacid or H2-antagonist administration
  • Drug distribution
    • CKD significantly increases or decreases volume of distribution.
    • Plasma protein binding of acidic drugs (e.g., warfarin, phenytoin) is decreased in end-stage renal disease (ESRD).
      • Monitor drug concentrations of free (unbound) drug.
    • Binding of basic drugs (e.g., quinidine) is usually normal or slightly increased or decreased.
    • Method to calculate volume of distribution (VD) can be influenced by renal disease.
      • Use distribution at steady state (VSS) to compare patients with renal insufficiency to others with normal renal function.
      • VSS is independent of drug elimination.
  • Metabolism
    • CKD may decrease nonrenal clearance of drugs to greater degree than seen in AKI (Table 1).
    • Severe renal insufficiency can cause accumulation of metabolites that contributes to pharmacologic activity or toxicity.
  • Excretion
    • Renal clearance of drug is composite of GFR, tubular secretion, and reabsorption.
    • Importance of altered renal function on drug elimination depends on fraction of drug normally eliminated unchanged by kidneys and degree of renal insufficiency.
    • Difficult to quantify contribution of tubular function to renal drug clearance.
    • Clinical measurement or estimation of CLcr or GFR remains guiding factor for drug dosage regimen design.

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Table Graphic Jump Location
Table 1. Nonrenal Clearance of Many Drugs Is Reduced in Patients with End-Stage Renal Disease

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