Calculating an appropriate dosing rate for a patient with renal impairment requires the clinician to consider several factors involving the patient and the drug:

Changes in renal clearance are correlated with changes in creatinine clearance (ClCR) by a constant q, which is different for each drug.

equation_11a_s.gif
 

Total drug clearance (CLT) is the sum of renal clearance (CLR) plus nonrenal clearance (CLN).

equation_11b_s
 

Steady-state mean drug plasma concentration (Css) is equal to dosing rate (D) divided by total clearance.

equation_11c_s
 

Rearranging this equation leads to

equation_11d_s.gif
 

Thus, the simplest approach to adjusting dosing rate in renal insufficiency is to:

  1. empirically determine q for the drug
  2. measure creatinine clearance for the individual
  3. select a desired plasma concentration
  4. calculate dose from the above equations

Although simple, this approach fails to account for differences in age and weight and for changes in volume of distribution, bioavailability, and nonrenal clearance that may occur in renal insufficiency. Roland and Tozer41 have described a more complete method for dosage adjustment in renal failure, using:

  • volume of distribution of the unbound drug in healthy subjects
  • volume of distribution of unbound drug in renal insufficiency
  • fraction of drug absorbed in healthy subjects
  • fraction of drug absorbed in renal insufficiency
  • ratio of the individual patient’s creatinine clearance to normal creatinine clearance
  • fraction of unchanged drug eliminated renally in healthy subjects
  • age
  • weight

Other complex methods of adjusting dosing regimen in renal failure are reviewed by Matzke and Millikin.29

All available methods for computing dosing regimens in renal insufficiency have errors. The actual plasma drug concentration obtained with the calculated dosing rate may vary considerably from the desired plasma concentration. The patient and the drug plasma concentration must be monitored and the dosing rate may need to be modified from the calculated rate.

Adapted from: Browne TR. Renal disorders. In: Ettinger AB and Devinsky O, eds. Managing epilepsy and co-existing disorders. Boston: Butterworth-Heinemann; 2002;49-62. With permission from Elsevier (www.elsevier.com).

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Reviewed By: 
Steven C. Schachter, MD
on: 
Sunday, February 1, 2004