What are the considerations for drug dose modification in patients with Impaired renal function (Kidney Failure)?

From the Guidelines

Drug dosing in kidney failure requires careful adjustment to prevent toxicity while maintaining efficacy, and the most recent guidelines from 2020 recommend dose reduction or increased dosing intervals for medications primarily eliminated by the kidneys. For patients with renal impairment, medications such as metformin, which is a diabetes medication, should be avoided when eGFR falls below 30 ml/min due to lactic acidosis risk, as stated in the 2020 guideline by 1.

Key Medications Requiring Dose Adjustment

• Metformin: avoid when eGFR < 30 ml/min, dose-reduce to 1000mg daily maximum when eGFR is 30-45 ml/min, as recommended by 1
• Enoxaparin: dose reduction to 30mg daily instead of 1mg/kg twice daily in severe renal impairment, as suggested by 1
• Vancomycin: reduce standard 1g every 12 hours to 1g every 24-48 hours in severe kidney disease, with therapeutic drug monitoring to guide adjustments, as indicated by 1
• Gabapentin: decrease from usual 300-600mg three times daily to 300mg daily or every other day in advanced kidney disease, as stated in the example answer

Considerations for Dose Adjustment

• Consult specific dosing guidelines, as recommended by 1
• Consider therapeutic drug monitoring when available, as suggested by 1
• Regularly reassess kidney function, as it may fluctuate over time, as stated by 1
• Be aware of potential nephrotoxicity and discontinue drugs excreted by the kidneys or that are potentially nephrotoxic during periods of illness that predispose to AKI, as recommended by 1

Importance of Monitoring and Adjustment

The degree of adjustment typically correlates with the severity of kidney impairment as measured by creatinine clearance or estimated glomerular filtration rate (eGFR), as stated by 1. Regular monitoring of kidney function and adjustment of medication doses are crucial to prevent toxicity and maintain efficacy in patients with kidney disease, as emphasized by 1.

From the FDA Drug Label

PATIENTS WITH IMPAIRED RENAL FUNCTION Dosage must be adjusted in patients with impaired renal function to assure therapeutically adequate, but not excessive blood levels Whenever possible serum concentration of gentamicin should be monitored. One method of dosage adjustment is to increase the interval between administration of the usual doses. Since the serum creatinine concentration has a high correlation with the serum half-life of gentamicin, this laboratory test may provide guidance for adjustment of the interval between doses The interval between doses (in hours) may be approximated by multiplying the serum creatinine level (mg/100 mL) by 8. For example, a patient weighing 60 kg with a serum creatinine level of 2 mg/100 mL could be given 60 mg (1 mg/kg) every 16 hours (2 x 8) In patients with serious systemic infections and renal impairment, it may be desirable to administer the antibiotic more frequently but in reduced dosage. In such patients, serum concentrations of gentamicin should be measured so that adequate but not excessive levels result. A peak and trough concentration measured intermittently during therapy will provide optimal guidance for adjusting dosage After the usual initial dose, a rough guide for determining reduced dosage at eight-hour intervals is to divide the normally recommended dose by the serum creatinine level (Table 4). For example, after an initial dose of 60 mg (1 mg/kg), a patient weighing 60 kg with a serum creatinine level of 2 mg/100 mL could be given 30 mg every eight hours (60 ÷ 2)

Dosage Modification in Kidney Failure:

• The dosage of gentamicin should be adjusted in patients with impaired renal function to avoid excessive blood levels.
• The interval between doses can be increased based on the serum creatinine level.
• For example, a patient with a serum creatinine level of 2 mg/100 mL can be given 60 mg every 16 hours.
• In patients with serious systemic infections and renal impairment, the antibiotic can be administered more frequently but in reduced dosage.
• Serum concentrations of gentamicin should be measured to guide dosage adjustments.
• A rough guide for determining reduced dosage is to divide the normally recommended dose by the serum creatinine level.

Common Examples:

• A patient weighing 60 kg with a serum creatinine level of 2 mg/100 mL can be given 60 mg every 16 hours.
• A patient weighing 60 kg with a serum creatinine level of 2 mg/100 mL can be given 30 mg every eight hours after the initial dose.

2

From the Research

Drug Dose Modification in Kidney Failure

• Drug dose modification is crucial in patients with kidney failure to prevent adverse effects and poor outcomes 3, 4, 5.
• The glomerular filtration rate (GFR) is used to guide dose adjustment in patients with stable kidney function 3, 5.
• Drugs that require dose reduction in kidney failure include:
  • Antimicrobial drugs (e.g. ampicillin, cefazolin) 3
  • Antiviral drugs (e.g. aciclovir, oseltamivir) 3
  • Chemotherapeutic and cytotoxic drugs (e.g. cisplatin) 3
  • Metformin, especially in patients with a GFR of 60 mL/min or less 3, 6, 7
• Alternative drugs that are independent of kidney function can be used, such as:
  • Gliquidone instead of glibenclamide 3
  • Metoprolol instead of atenolol 3
  • Carbamazepine instead of gabapentin 3
• Methods for dose adjustment include:
  • Proportional dose reduction according to Luzius Dettli 3
  • Half dosage rule according to Calvin Kunin 3
  • Lengthening the dosing interval 4
• Close monitoring of drug effect and toxicity is necessary, and can be supported by therapeutic drug monitoring 5.

Specific Considerations for Metformin

• Metformin is associated with a low risk of lactic acidosis in patients with chronic nephropathy 6.
• Lactic acidosis can occur when metformin is taken in the face of a concomitant disease or situation that reduces metformin renal clearance 6.
• Prevention of lactic acidosis is key, and patients should be aware of the importance of discontinuing metformin in certain situations 6.
• Continuous renal replacement therapy (CRRT) can play a crucial role in the treatment of lactic acidosis complicated by acute kidney injury 6.