13.21: Drug Dosing in Renal Diseases: Dose Adjustments Based on Drug Clearance and Elimination Rate Constant

In patients with renal disease, dosage adjustments are necessary to maintain therapeutic plasma drug concentrations and prevent toxicity or subtherapeutic exposure. Renal impairment alters drug pharmacokinetics, especially in conditions like uremia, where changes such as prolonged elimination half-life and altered apparent volume of distribution can significantly affect drug disposition. These changes require careful modification of the dosing regimen to achieve the desired clinical outcomes.

One commonly used approach involves evaluating changes in total body clearance. Since clearance is a significant determinant of steady-state drug concentration, any reduction due to impaired kidney function necessitates proportional dose adjustments. In patients receiving intravenous infusions, the infusion rate must be recalculated to match the reduced renal clearance in uremic individuals, ensuring plasma concentrations remain within the therapeutic range.

Another strategy considers changes in the elimination rate constant, which typically decreases in renal impairment. In the context of a multiple-dose regimen, if both the dosing interval and the apparent volume of distribution are kept unchanged, the dose for a uremic patient becomes a fraction of the dose used in individuals with normal renal function. This fractional dose ensures that drug accumulation does not exceed safe limits over time.

When the elimination rate constant cannot be directly measured, it is expressed as the sum of the renal and nonrenal elimination rate constants. In such cases, standard pharmacokinetic assumptions can be used to derive a substituted final equation that helps estimate the appropriate dose for renal-impaired patients. These adjustments are critical for maintaining drug efficacy and minimizing the risk of adverse effects, especially for drugs with narrow therapeutic windows or those primarily excreted by the kidneys. Proper individualized dosing ensures optimal therapy and supports safe drug administration in patients with compromised renal function.

In renal disease, dosage adjustments are essential to maintain therapeutic plasma drug concentrations.

Pharmacokinetic changes in uremia, such as prolonged elimination half-lives and altered apparent volume of distribution, require careful dosage regimen modification.

One approach to dose adjustment focuses on changes in total body clearance.

To maintain the desired average concentration in uremic patients, the dose must be adjusted accordingly.

For intravenous infusions, maintaining a steady-state concentration comparable to patients with normal renal function requires adjusting the infusion rate based on renal clearance in uremic patients.

Another method adjusts for decreased elimination rate constant in uremic patients.

In a multiple-dose regimen, where the apparent volume of distribution and dosing interval remain constant, the uremic dose becomes a fraction of the normal dose.

When the elimination rate constant cannot be measured directly, it is the sum of the nonrenal rate and renal rate constants. By rearranging the renal clearance equation and using specific assumptions and substitutions, the overall elimination rate constant can be calculated.