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Renally excreted drug dosing

I. Introduction

Renal function declines with age as a result of the anatomical and physiological changes that occur with aging. Because renal function deteriorates with age, even in the seemingly healthy patient, clearance of renally excreted and metabolized drugs may be markedly impaired in the elderly patient. Therefore, to avoid toxic effects a dosage reduction is often necessary.1,2

Because both the production and excretion of creatinine decreases with age, an elderly patient can have markedly decreased renal function without having an elevated serum creatinine level. Thus, an estimate of creatinine clearance is necessary for determining the appropriate dosage of renally excreted drugs. Creatinine clearance can either be measured by a timed urine collection or estimated from serum creatinine.1,2

Timed urine collections are associated with significant collection errors, due to improper timing and missed samples. Timed overnight collections or shorter timed daytime collections may reduce the inconvenience of a 24-hour collection, but are still associated with collection errors.

Creatinine clearance equations
An accurate, reliable and unbiased method for calculating creatinine clearance from serum creatinine is much sought after by clinicians. Dozens of methods for estimating creatinine clearance have been published, but no single method is ideal for all patients. Furthermore, much controversy exists as to which method is best for a particular patient group.

In adults, the Cockcroft and Gault equation has become the defacto standard despite many documented problems.5,6,7,8 C&G produces consistent results in patients of average size and build, with stable renal function and a SCr less than 3 mg%. However, it is problematic in others.

The C&G equation was derived from a group of lean males, bringing into question the validity of this method in obese patients. The Salazar and Corcoran equation was derived from an obese patient population, and may be more appropriate for this group.16

In patients with unstable renal function, Jelliffe's multi step method may be more accurate. This method corrects for rising SCr and for chronic renal failure.15

The MDRD method was derived from a study of a large diverse patient population having a wide range of renal function. The MDRD equations have also been validated in a separate, equally large and diverse group. Therefore, some feel that MDRD is the most accurate CLCR method overall.26, 27 Nevertheless, for dosing purposes, NKDEP does not recommend using the MDRD study equation at this time because the clinical impact on drug dose adjustment has not been compared to current practice. Pharmacists should continue to use their current drug dosing methods.28

In children 12 and older, the Cockcroft and Gault equation gives a reasonably accurate estimate of creatinine clearance. For younger children, infants and neonates, no method of estimating CLCR is reliable. The Swartz equation is the standard equation for young children, however, the results are not consistent enough to be used for pk modeling.20

Dosing guidelines
Dosage adjustment guidelines which are based on creatinine clearance have been published.3,4 Manufacturers are now required by FDA to provide dosage guidelines for patients with decreased creatinine clearance.

A dosage regimen may be adjusted either by lowering the dose or prolonging the dosage interval. The dosage reduction method is recommended for those drugs for which a relatively constant blood level is desired, e.g., beta-lactam antibiotics. The interval extension method is recommended for those drugs whose efficacy is related to the peak level, e.g., fluoroquinolone antibiotics.

II. Monitoring Parameters

The following screening criteria may be used to identify patients who are at risk of impaired renal function:

  1. Age 65 years and over
  2. Elevated serum creatinine

III. Precautions

  1. The following conditions may falsely elevate serum creatinine, thereby falsely decreasing the creatinine clearance.
    1. Dehydration
    2. Drugs:
      1. Cephalosporins
      2. Cimetidine
      3. Trimethoprim-sulfa

  2. The following conditions may falsely decrease serum creatinine, thereby falsely elevating the creatinine clearance.
    1. Muscular diseases (muscular dystrophy, polymyositis, rhabdomyolysis)
    2. Small muscle mass (due to atropy or amputation, cachexia or malnutrition)
    3. Liver disease (cirrhosis)

  3. Other precautions

    Obesity
    Cockcroft & Gault derived their equation from a group of 296 males, all within 10% of LBW, leading many to question the validity of this method in obese patients. Studies have generally found that use of TBW (total body weight) tends to over-estimate CLCR in obese patients, while use of LBW (lean body weight) tends to under-estimate CLCR.17 Various weight correction factors have been proposed, each has their proponents and detractors:

    1. Use of LBW plus 20 to 40% of the excess weight.
    2. Normalizing to 72 kg.
    3. Normalizing to BSA of 1.73 M2

    An alternative for this group is the Salazar and Corcoran method which was derived from an obese patient population.16

    Elderly
    The Cockcroft & Gault equation tends to over-estimate CLCR in the elderly.12 Therefore, an empiric "correction" commonly employed is to round up the serum creatinine to 1.0 mg% in elderly patients. However, most studies have found this to be an inappropriate practice which under-estimates true CLCR.13

    Very low serum creatinine
    Use of a very low serum creatinine (0.5 mg% or less) in the C&G equation leads to a falsely elevated CLCR. Therefore, many practitioners designate 0.7 mg% 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.15

    Women
    As stated above, C&G derived their equation from a group of men, the 0.85 factor for women was added afterwards, to correct for the smaller muscle mass of females. One study found that a 0.9 factor for women may be more accurate.10

    Diet
    Serum creatinine will be affected by dietary extremes. Patients who are following an unusual vegetarian diet may have a lower SCr than expected. A diet excessively rich in red meat will lead to the reverse error.

IV. Program procedure

After selecting the drug, click on the Prospective dosing tab to view the dosing table. The program asks for the current dosage. This is necessary if recommending a dosage adjustment, otherwise, if determining an initial dosage, just leave blank. Next type in your dosage recommendation.

For some drugs a one-compartment model may be selected. If a one compartment model is selected, the program calculates an ideal dose, based on the dosing weight and creatinine clearance. After the user enters a practical dose and interval, the program calculates estimated steady state peak and trough levels. If an MIC is entered, PK/PD parameters will be calculated. For more information on this subject, please see this page:

V. Renal drug dosing flow chart

VI. Pharmacokinetic formulas

The drug models are not hard-coded into the program. The parameters are found in the drug model database and are fully user-edit able. You can tailor each drug model to fit your patient population, or you can create your own models. See the Edit drug models section of the help file for further information.

  1. Calculate lean body weight (LBW)21
    LBW (Males) = 50 + (2.3 x Height in inches over 5 feet)
    LBW (Females) = 45.5 + (2.3 x Height in inches over 5 feet)

  2. Calculate adjusted body weight (ABW)
    Because creatinine is a by-product of muscle metabolism, excess weight in the form of adipose tissue, does not significantly affect the production of creatinine. Therefore, lean body weight or an adjusted body weight is used for CLCR calculations.

    ABW = LBW + [CF x (TBW - LBW)]
    . . . where CF = correction factor (usually 20 to 40%)
    . . . where WT = patient's total weight

  3. Calculate body surface area (BSA)22
    BSA = 0.007184 x (HT0.725 + WT 0.425)
    . . . where HT = height in centimeters
    . . . WT = weight in kilograms

  4. Jelliffe Multi-step method15
    1. Estimate urinary creatinine excretion rate (E)
      E (males) = LBW x (29.305 -[0.203 x (age)])
      E (females) = LBW x (25.3 -[0.18 x (age)])

    2. Correct E for nonrenal creatinine excretion in chronic renal failure
      E = E x [1.035 - 0.0377(SCr)]
      . . . where SCr is the latest serum creatinine OR if SCr is rising, the average SCr

    3. Correct E for rising serum creatinine
      E = E - [4 x LBW x (SCr1-SCr2)] / D
      . . . where LBW = lean body weight in kilograms
      . . . SCr1= the latest serum creatinine
      . . . SCr2= the earlier serum creatinine
      . . . D = the number of days between

    4. Calculate normalized creatinine clearance (CLCR)
      CLCR/1.73 M2 = (E * 0.12) / (SCr * BSA)
      . . . where BSA is body surface area in M2

  5. Cockcroft and Gault equation23
    CLCR Males = ABW(140 - Age) / (SCr x 72)
    CLCR Females = 85% of male value
    . . . where SCr is the most recent serum creatinine.
    . . . ABW = adjusted body weight

  6. Calculate dosage
    Option 1 - Dosing table
    Dosage tables are derived from either the FDA approved package insert, Bennett's tables, AHFS Drug Information, or Critical Care Pharmacotherapy. An example of a dosing guideline from the package insert is shown in Table 1. An example of a dosing table is shown in Table 2.3

    Table 1. Manufacturer's dosage recommendation for Neurontin®
    CLCR
    (mL/min)     		Total Daily Dose
    (mg/day)     		Dose Regimen (mg)
    >/=60 900-3600 300 TID 400 TID 600 TID 800 TID 1200 TID
    >30-59 400-1400 200 BID 300 BID 400 BID 500 BID  700 BID
    >15-29 200-700 200 QD  300 QD  400 QD  500 QD   700 QD
    15a 100-300 100 QD  125 QD  150 QD  200 QD   300 QD
    a For patients with creatinine clearance <15 mL/min, reduce daily dose in proportion to creatinine clearance (e.g., patients with a creatinine clearance of 7.5 mL/min should receive one-half the daily dose that patients with a creatinine clearance of 15 mL/min receive).

    Table 2. Dosage adjustment for renal impairment
    Drug Method CLCR > 50ml/min CLCR 10 to 50ml/min CLCR < 10ml/min
    Acyclovir I 5mg/kg Q 8 hr 5mg/kg Q 12 hr 5mg/kg Q 24 hr
    Ampicillin D, I 1-2 g Q 6 hr 0.5 g Q 6-8 hr 0.5-1g Q 12 hr
    Aztreonam D, I 1-2 g Q 6-8 hr 0.5-1g Q 8 hr 0.5-1g Q 12 hr
    Cefazolin D, I 1-2 g Q 6-8 hr 1-2 q Q 12-24 hr 1 g Q 48 hr
    Cefotetan D, I 1-2 g Q 12 hr 1-2 g Q 12-24 hr 0.5 - 1g Q 24 hr

    Option 2 - One compartment model
    If parameters are available, a one compartment model may be employed. Model parameters for common antibiotics are listed in Table 3.25

    Table 3. One-compartment model parameters
    Drug Target peak/trough A B C
    Acyclovir 40/10 0.035 0.002 0.217
    Ampicillin 50/ 5 0.058 0.0064 0.26
    Azlocillin 250/25 0.116 0.0058 0.16
    Aztreonam 100/10 0.116 0.0023 0.143
    Carbenicillin 200/20 0.046 0.0042 0.346
    Cefamandole 60/ 6 0.043 0.0065 0.216
    Cefazolin 120/20 0.032 0.0026 0.15
    Cefonicid 150/25 0.014 0.0016 0.10
    Ceforanide 120/20 0.023 0.0021 0.132
    Cefotaxime 80/ 4 0.069 0.0056 0.159
    Cefotetan 120/20 0.02 0.00178 0.125
    Cefoxitin 60/ 6 0.035 0.0066 0.216
    Ceftazidime 60/ 6 0.028 0.0034 0.237
    Ceftizoxime 60/ 6 0.028 0.0046 0.229
    Cefuroxime 60/ 8 0.041 0.0051 0.174
    Cephalothin 50/ 5 0.06 0.0114 0.26
    Cephaparin 50/ 5 0.06 0.0092 0.24
    Cephradine 50/ 5 0.06 0.0065 0.26
    Imipenem 40/ 1 0.173 0.0052 0.162
    Methicillin 40/ 4 0.173 0.0075 0.305
    Mezlocillin 250/25 0.173 0.0052 0.155
    Piperacillin 250/25 0.173 0.0052 0.156
    Ticarcillin 200/20 0.043 0.0053 0.336

    1. Calculate elimination rate constant (Kel) using A & B from Table 2.
      Kel = A + (CLCR x B)
      . . . where CLCR = Creatinine clearance

    2. Calculate dosing weight (DW)
      DW = LBW + CF x (ABW-LBW)
      . . . where ABW = patient's true weight
      . . . LBW = lean body weight
      . . . CF = correction factor

    3. Calculate volume of distribution (Vd) using C from Table 2.
      Vd = DW * C

    4. Calculate ideal dosing interval (tau)
      tau = tinf + -1 / Kel x ln (Cpmin/Cpmax)
      . . . where Cpmin = Target trough
      . . . Cpmax = Target peak

    5. Calculate ideal maintenance doses
      MD = Kel x Vd x Cpmax x tinf x (1 - e-Kel x tau / 1 - e-Kel x tinf)

    6. User selects practical dosage and interval

    7. Calculate expected peak & trough levels
      Peak = MD / tinf x Vd x Kel x (1 - e-Kel x tinf / 1 - e-Kel x tau)
      Trough = Peak * e-Kel x (tau - tinf)

    The one feature that the RxKinetics family of pk programs have in common is the ability to edit the default drug models. You can edit any model to better fit your patient population, you can even add your own 1-compartment models for any drug and for multiple patient populations, a "Swiss army knife" for clinical pharmacokinetics if you will. Please see the following tutorial for a basic overview of how to create a one compartment model:

VII. Bibliography

  1. Lipman AG. Drug Therapy Considerations in the Renally Compromised Geriatric Patient. Consultant Pharmacist 1987;Supp B:3-7.
  2. Caldwell JR. Alterations in Renal Function in the Elderly Population: Implications for Medication Prescribing. Consultant Pharmacist 1987;Supp B:3-7.
  3. Chernow, Bart Pocket Book of Critical Care Pharmacotherapy 1st edition. Lippincott, Williams & Wilkins, 1995.
  4. Aronoff George R, et al. Drug Prescribing in Renal Failure. Philadelphia, PA. ACP, 1999.
  5. Lott RS, Hayton WL. Estimation of Creatinine Clearance from Serum Creatinine Concentration - a review. Drug Intell Clin Pharm 1978;12:140-150.
  6. Sawyer WT, et al. Variables Affecting Creatinine Clearance Prediction. Am J Hosp Pharm 1983;40:2175-80.
  7. Rhodes PJ, et al. Evaluation of Eight Methods for Estimating Creatinine Clearance in Men. Clin Pharm. 1987;6:399-406.
  8. Chow MS, Schweizer R. Estimation of Creatinine Clearance in Patients with Unstable Serum Creatinine Concentrations: Comparison of Multiple Methods. Drug Intell Clin Pharm 1985;19:385-390.
  9. Hull JH, et al. Influence of range of renal function and liver disease on predictability of creatinine clearance. Clin Pharmacol Ther. 1981 Apr;29(4):516-21. [ PubMed ]
  10. Canaday BR, et al. Fractional Adjustment of Predicted Creatinine Clearance in Females. Am J Hosp Pharm 1984;41:1842-3. [ PubMed ]
  11. Melamed AJ, Vanamee P. Estimating creatinine clearance in patients with cancer. Hosp Pharm 1988;23:898-901.
  12. Drusano GL, et al. Commonly used methods of estimating creatinine clearance are inadequate for elderly debilitated nursing home patients. J Am Geriatr Soc. 1988 May;36(5):437-41. [ PubMed ]
  13. Smythe M, Hoffman J, Kizy K, Dmuchowski C. Estimating creatinine clearance in elderly patients with low serum creatinine concentrations. Am J Hosp Pharm. 1994 Jan 15;51(2):198-204. [ PubMed ]
  14. Lau AH, et al. Estimation of creatinine clearance in malnourished patients. Clin Pharm 1988:7;62-65. [ PubMed ]
  15. Jelliffe RW, Jelliffe SM. Estimation of creatinine clearance in patients with unstable renal function. (revised). Originally published: A computer program for estimation of creatinine clearance from unstable serum creatinine concentration. Math Biosci. 14:17-24 (June) 1972.
  16. 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. [ PubMed ]
  17. Dionne RE, Bauer LA, Gibson GA, Griffen WO Jr, Blouin RA. Estimating creatinine clearance in morbidity obese patients. Am J Hosp Pharm. 1981 Jun;38(6):841-4. [ PubMed ]
  18. Paap CM, Nahata MC. Prospective evaluation of ten methods for estimating creatinine clearance in children with varying degrees of renal dysfunction. J Clin Pharm Ther. 1995 Apr;20(2):67-73. [ PubMed ]
  19. Hernandez de Acevedo L, Johnson CE. Estimation of creatinine clearance in children: comparison of six methods. Clin Pharm. 1982 Mar-Apr;1(2):158-61. [ PubMed ]
  20. Pierrat A, Gravier E, Saunders C, Caira MV, Ait-Djafer Z, Legras B, Mallie JP. Predicting GFR in children and adults: a comparison of the Cockcroft-Gault, Schwartz, and MDRD formulas. Kidney Int. 2003 Oct;64(4):1425-36. [ PubMed ]
  21. Devine Ben. Gentamicin therapy. Drug Intell Clin Pharm 1974;8:650-6.
  22. DuBois D, DuBois EF. A formula to estimate the approximate surface area if height and weight be known. Arch Intern Medicine. 1916; 17:863-71.
  23. Cockroft D.W., Gault M.H. Prediction of creatinine clearance from serum creatinine. Nephron. 1976;16(1):31-41. [ PubMed ]
  24. Pai MP, Paloucek FP. The origin of the "ideal" body weight equations. Ann Pharmacother. 2000 Sep;34(9):1066-9. [ PubMed ]
  25. Zaske D, Lesar T. "Other Anti-Infective Agents" in A Textbook for the Clinical Application of Therapeutic Drug Monitoring, Taylor and Caviness (Ed). Abbott Laboratories, Irving, TX. 1986.
  26. Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D. A more accurate method to estimate glomerular filtration rate from serum creatinine: A new prediction equation. Modification of Diet in Renal Disease Study Group. Ann Intern Med 130:461-470, 1999. [ PubMed ]
  27. Levey AS, Greene T, Kusek JW, Beck GJ. A simplified equation to predict glomerular filtration rate from serum creatinine. J Am Soc Nephrol 11:A0828, 2000 (abstr)
  28. Gary L. Myers, W. Greg Miller, Josef Coresh, et al. Recommendations for Improving Serum Creatinine Measurement: A Report from the Laboratory Working Group of the National Kidney Disease Education Program. Clinical Chemistry 2006;52(1):5-18. [ PDF ] [ Summary ]

VIII. Recommended Reading

  1. Aronoff George R, et al: Drug Prescribing in Renal Failure. Philadelphia, PA. ACP, 1999.
  2. Bauer, Larry A. Applied Clinical Pharmacokinetics. McGraw-Hill. 2001.
  3. Evans W, Schentag J, Jusko J (eds): Applied Pharmacokinetics 3rd edition. San Francisco, CA. Applied Therapeutics, 1992.
  4. Chernow, Bart Pocket Book of Critical Care Pharmacotherapy 1st edition. Lippincott, Williams & Wilkins, 1995.

IX. Additional WWW Resouces

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