Chronic Kidney Disease–Drug Therapy Individualization

SOURCE

Source: Battistella M, Matzke GR. Drug therapy individualization for patients with chronic kidney disease. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM, eds. Pharmacotherapy: A Pathophysiologic Approach. 10th ed. New York, NY: McGraw-Hill; 2017. http://accesspharmacy.mhmedical.com/content.aspx?bookid=1861&sectionid=146061579. Halilovic J, Dager W. Acute kidney injury. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM, eds. Pharmacotherapy: A Pathophysiologic Approach. 10th ed. New York, NY: McGraw-Hill; 2017. http://accesspharmacy.mhmedical.com/content.aspx?bookid=1861&sectionid=134127206. Accessed May 18, 2017.

GENERAL PRINCIPLES

• 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 (CL_cr) 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.

EFFECT OF CKD ON DRUG DISPOSITION

• Drug absorption.

  • Little quantitative information available.

  • Bioavailability theoretically affected by:

    • Drug interactions.

    • Delayed gastric emptying.

    • Reduced gastric acidity.

    • Edema of GI tract.

    • Concomitant drug therapy, especially antacid, H₂-antagonist, and phosphate binder administration.

• Drug distribution.

  • CKD significantly increases or decreases volume of distribution.

  • Plasma protein binding of acidic drugs (eg, penicillins, cephalosporins, furosemide, phenytoin) is decreased due to hypoalbuminemia, qualitative changes in the conformation of the protein binding site, and/or competition for binding sites by other drugs, metabolites, and endogenous substances.

    • Monitor drug concentrations of free (unbound) drug.

  • Binding of basic drugs (eg, bepridil, disopyramide) is usually normal or slightly increased or decreased.

  • Method to calculate volume of distribution (V_D) can be influenced by renal disease.

    • Use distribution at steady state (V_SS) to compare patients with renal insufficiency to others with normal renal function.

    • V_SS 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 CL_cr or GFR remains guiding factor for drug dosage regimen design.