Nephrology Hypertension

Pharmacology and Toxicology: Principles of Drug Dosing in Chronic Kidney Disease/End-Stage Renal Disease

Does this patient have chronic kidney disease requiring drug dosage modification?

Do I have to modify medication dosing or dosing interval in my patient with chronic kidney disease?

In general, the requirement for dose adjustment depends on the primary route of elimination of the drug. In the simplest case, a drug that is cleared renally without metabolism, a linear relationship may exist between change in drug exposure and change in Clcr (R&T 3rd ed 1995 156-183). However, most drugs are metabolized to some degree and are eliminated by a combination of renal and hepatic pathways.Other factors must be considered, including associated changes in gastrointestinal tract integrity that may alter drug absorption, and changes in serum albumin concentrations that may alter the proportion of free:protein bound drug, leading to an increased volume of distribution.

It is important to note that changes in drug exposure of agents that are primarily hepatically metabolized are also observed in patients with chronic kidney disease (CKD), possibly due to alterations in hepatic drug metabolism and transport caused by circulating uremic toxins.

FDA approved dosing guidelines for drugs that require dose adjustment in patients with CKD are provided by the manufacturer in the drug labeling. However, this drug-dose individualization is often based on the patient’s estimated Clcr calculated using the Cockraft-Gault equation. Some institutions report Modification of Diet in Renal Disease (MDRD) estimated glomerular filtration rate (eGFR) values, and it is unclear whether or not these values are interchangeable.

The following stepwise approach to adjusting drug dosing is often recommended for patients with CKD:

  1. Obtain medical and medication history, relevant demographics and clinical information

  2. Estimate creatinine clearance using Cockraft-Gault equation

  3. Review current medications and identify drugs that require individualization

  4. Calculate individualized treatment regimen using pharmacokinetic parameters and patient’s renal function

  5. Monitor parameters of drug response and toxicity

  6. Adjust regimen based on efficacy/toxicity and change in renal function as necessary

How should patients with chronic kidney disease requiring drug dosing alteration be managed?

CKD is often a progressive condition with renal function declining over time.However, glomerular function and tubular secretion do not always decline in parallel in some patients.There has also been some concern that drugs eliminated primarily by secretion are subject to intracellular accumulation in the proximal tubule epithelium if the balance of uptake and efflux transport is disrupted by co-administered medications or accumulating uremic solutes. Therefore, drug dosing must be periodically re-evaluated, and each drug must be adjusted individually with regard to efficacy and the potential for toxicity (which is to say that all renally cleared medications cannot be arbitrarily dose adjusted by the same percentage).

What is the mechanism for altered drug absorption, and how do I know if this will be problematic in a chronic kidney disease patient?

The mechanism and extent of altered bioavailability in CKD patients is not well understood.Several mechanisms have been proposed, including:

  • Change in gastric pH due to pathophysiology or antacid administration

  • Gastrointestinal hyper- or hypo- motility

  • Vomiting or diarrhea secondary to CKD or CKD treatment

Many pharmacokinetic changes are observed in CKD patients; some of these changes may be a result of altered absorption, and both Cmax and tmax can be variable.

An increase in bioavailability in end-stage renal disease (ESRD) patients (due to decreased first-pass metabolism) has been observed for some β-blockers, dextropropoxyphene, and dihydrocodeine, and has resulted in adverse clinical consequences.

What causes a change in volume of distribution in chronic kidney disease, and how do I know what drugs might be affected?

Volume of distribution (VD) is a non-physiologic proportionality constant that relates the amount of drug in the body to the serum concentration. A low VD indicates that the drug remains mostly in the circulating bloodstream, whereas a high VD indicates that the drug distributes mainly to the tissues with little drug remaining in the circulation. VD can be calculated using the following equation (Figure 1).

Figure 1

Calculating volume of distribution

Where Vb and Vt are the volumes of blood and tissues, and fb and ft are the fractions of unbound drug in the blood and tissues, respectively.

Drugs administered to CKD patients may exhibit altered VD parameters—this may result in unpredictable drug exposure. Although the total plasma concentration may be within normal limits for non-CKD patients, the concentration of unbound drug at the site of pharmacologic action may be sub- or supra- therapeutic in the CKD patient. When possible, unbound drug concentrations should be monitored for drugs that are highly protein bound (< 20% unbound) and have a narrow therapeutic index (eg, phenytoin, disopyramide).

In patients with CKD, an increase in VD may be caused by:

  1. Decreased protein binding

  2. Increased tissue binding

  3. Altered body composition (variable total-body water vs. total body weight).

In general, protein binding of acidic drugs (including warfarin, phenytoin, ceftriaxone, and furosemide) is decreased in patients with CKD due to structural changes of protein binding sites, displacement by endogenous compounds, and decreased serum albumin concentration. The binding of basic drugs is unpredictably affected by CKD, with some basic drugs exhibiting a slightly decreased VD (including bepridil, clonidine, and propafenone), and some exhibiting an increased VD (including diazepam, triamterene, prazosin, and chloramphenicol). Altered tissue binding may be caused by the displacement of drug from tissue binding sites by endogenous compounds such as circulating uremic toxins or other co-administered medications.

What changes in hepatic metabolism and transport can occur in a patient with chronic kidney disease?

A patient with decreased kidney function will understandably require dose-adjustment for drugs that are cleared primarily by renal excretion; however the significance of altered non-renal drug disposition in CKD patients is only beginning to be appreciated. Recent in vitro and in vivo studies have suggested that inhibition of CYP3A4, a hepatic monooxygenase, and P-glycoprotein (P-gp), a hepatic efflux transporter may contribute to the unpredictability of drug disposition; however, other studies have shown that CYP3A4 is not inhibited, and that inhibition or down regulation of hepatic organic anion transporters (OATP 1B1 or OATP 1B3) and/or P-gp is a more likely mechanism.

While the precise identity of the affected pathways will require further examination, hepatic metabolism and transport are clearly affected in patients with CKD, and caution should be exercised when administering drugs that have clearance pathways that depend on CYP3A4, P-gp, and OATP1B1/1B3.

How do I calculate an approximate dose and dosing interval for a drug?

Approximate dose/dosing intervals can be calculated using known pharmacokinetic parameters in normal individuals (elimination rate constant (k), total body clearance (CL), fraction eliminated unchanged renally (fe) and desired peak and trough levels) with adjustment for renal function 1. This method assumes that the change in CL and k are proportional to CLcr, that the drug exhibits first-order pharmacokinetics and does not account for changes in drug metabolism. Despite these limitations, this method does a reasonable job at determining a starting point for a dosing regimen.

  1. Calculate KF, the ratio of the patients estimated CLcr/normal CLcr (assumed to be 120 mL/min) (Figure 2)

    Calculating KF.

  2. Calculate Q, the pharmacokinetic dosing adjustment factor (Figure 3)

    Calculation of Q, the pharmacokinetic dosing factor.

  3. Where fe is the fraction eliminated unchanged renally in normal individuals.

  4. A drug maintenance dose and dosing interval can be calculated as follows (Figure 4):

    Calculation of modified dose and dosing interval.

  5. Where Df and τf are the dose and dosing interval for a patient with renal failure, and Dn and τn are the standard dose and dosing interval in normal individuals.

Note that these very basic equations do not include adjustments for altered VD and bioavailability, this more complex model is as follows, but is not commonly used in patient care settings (Figure 5).

Figure 5

A more complex model for dose adjustment.

Where F is bioavailability, Cpt is the desired plasma concentration at time t, VD is the volume of distribution, ka is the absorption rate constant, k is the elimination rate constant, and τ is the dosing interval.

What drugs are filtered out during peritoneal dialysis?

Managing drug regimens for patients on PD is less complicated than HD due to the fact that drugs are cleared less efficiently with PD. Compounds that are ionized at physiologic pH will diffuse across the peritoneal membrane more slowly than unionized compounds, and compounds that are not filtered out by HD will generally not be removed by PD.

As a general rule, drugs other than antibiotics used to treat peritonitis are dosed based on residual renal function as the additional clearance by PD is relatively small. For antibiotics used to treat peritonitis, refer to published dosing guidelines for the specific disease state.

What drugs are filtered out during hemodialysis?

There are multiple factors that need to be considered that may be drug related, or dialysis related.

Drug related

  • Molecular weight/size

  • Degree of protein binding

  • Volume of distribution

Dialysis related

  • Composition of dialysis membrane

  • Filter surface area

  • Blood/dialysate flow rates

  • High vs low flux conditions

In general, drugs that are highly protein bound (regardless of the molecular weight) and drugs with a high volume of distribution (indicating that the drug is compartmentalized in the tissue and not in the blood) are not well dialyzed. The exact molecular weight cutoff for unbound drug depends on the composition of the dialysis filter and the dialysis protocol.

Can clearance parameters in hemodialysis be calculated?

Parameters can be calculated by first using published dialysis clearance values (CLD) and the patient’s residual renal function (CLRES) to calculate the total clearance during dialysis (CLT) (Figure 6)

Figure 6.

Calculating total clearance during dialysis.

The half-life of the drug can then be calculated for the interval while the patient is being dialyzed and between dialysis treatments using published values for the volume of the distribution (VD) (Figure 7)

Figure 7

Calculating half-life on- and off-dialysis.

Using these values, the elimination rate constant (k) during or between dialysis treatments can also be calculated (Figure 8)

Figure 8

Calculating the elimination rate constant during or between dialysis.

And the plasma concentration can be estimated using the following relationship (Figure 9):

Figure 9

Estimating plasma concentration during or between dialysis.

For more detailed information, consult the chapter by Matzke and Frye on Drug Therapy Individualization for Patients with Renal Insufficiency (see What is the Evidence section below).

What is the evidence?

Rowland, M, Tozer, TN. Clinical Pharmacokinetics: Concepts and Applications.. Lea and Febiger. 1995.

(This mainstay textbook of pharmacokinetics addresses both basic and complex concepts in pharmacokinetics and is helpful for users desiring more in depth discussion of the mathematical derivations of pharmacokinetic parameters.)

Dowling, TC, Matzke, GR, Murphy, JE, Burckart, GJ. "Evaluation of renal drug dosing: prescribing information and clinical pharmacist approaches". Pharmacotherapy. vol. 30. 2010. pp. 776-786.

(This article contains very practical dosing recommendations for adjusting doses in patients with altered renal function.)

Matzke, GR, Frye, RF. "Drug therapy individualization for patients with renal insufficiency". Pharmacotherapy: A Pathophysiologic Approach. McGraw Hill. 2008.

(This well-known reference provides an overview of drug therapy individualization.)

Giacomini, KM, Huang, SM, Tweedie, DJ. "Membrane transporters in drug development". Nat Rev Drug Discov. vol. 9. 2010. pp. 215-236.

(This article provides a comprehensive review of relevant drug transporters in the kidney and other tissues involved in drug disposition.)

Yeung, CK, Shen, DD, Thummel, KE, Himmelfarb, J. "Effects of chronic kidney disease and uremia on hepatic drug metabolism and transport". Kidney Int. vol. 85. 2014 Mar. pp. 522-8.

(This review provides an overview of the effects of chronic kidney disease on hepatic drug metabolism and transport.)

Matzke, GR, Comstock, TJ, Evans, WE, Schentag, JJ, Burton, ME. " Influence of renal disease and dialysis on pharmacokinetics". Applied Pharmacokinetics: Principles of Therapeutic Drug Monitoring. Lippincott Williams & Wilkins. 2005.

Matzke, GR, Frye, RF. "Drug administration in patients with renal insufficiency. Minimising renal and extrarenal toxicity". Drug Saf. vol. 6. 1997. pp. 205-231.

Gibaldi, M, Koup, JR. "Pharmacokinetic concepts - drug binding, apparent volume of distribution and clearance". Eur J Clin Pharmacol.. vol. 20. 1981. pp. 299-305.

Sun, H, Frassetto, LA, Huang, Y, Benet, LZ. "Hepatic clearance, but not gut availability, of erythromycin is altered in patients with end-stage renal disease". Clin Pharmacol Ther. vol. 87. 2010. pp. 465-472.

Nolin, TD, Frye, RF, Le, P, Sadr, H, Naud, J, Leblond, FA, Pichette, V, Himmelfarb, J. "ESRD impairs nonrenal clearance of fexofenadine but not midazolam". J Am Soc Nephrol. vol. 20. 2009. pp. 2269-2276.

Trotman, RL, Williamson, JC, Shoemaker, DM, Salzer, WL. "Antibiotic dosing in critically ill adult patients receiving continuous renal replacement therapy". Clin Infect Dis. vol. 41. 2005. pp. 1159-1166.

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