Module 10. Effect of dysfunction of an organ of elimination on pharmacokinetics.
Having completed this exercise and based on pharmacokinetic constants and data, students should be able to:
- Describe the nature of dose adjustments that should be considered to safely and effectively treat infections using gentamicin in patients with reduced renal function.
- Describe the pharmacokinetic differences between and among (normal) adult, neonatal, and geriatric patients and patients with documented renal dysfunction.
Frazier DL; Aucoin DP; Riviere JE: Gentamicin pharmacokinetics and nephrotoxicity in naturally acquired and experimentally induced disease in dogs. J Am Vet Med Assoc (HAV), 1988 Jan 1; 192 (1): 57-63.
Occasionally (geriatric animal that acquires an infection while on adequate doses of enrofloxacin) it is necessary to use aminoglycoside antibiotics in the presence of renal dysfunction. It is important that appropriate doses and intervals are used in order to produce safe and effective therapy.
Download gentamicinrenalfailure.xlsx, the spreadsheet for this exercise. Depending on your settings, you may have to "enable editing" in order to make the changes suggested by the exercise.
Pharmacokinetic variables on the worksheet are preset for four dogs with different degrees of renal dysfunction. The patients approximate:
- #1, a "normal" dog (no loss of renal function)
- #2, a dog with 50% renal function (a loss of renal function that is clinically undetectable)
- #3, a dog with 33% renal function (detectable loss of function)
- #4, a dog with 15% renal function (significant renal disease/failure)
Dosages are set to allow you to reveal graphical and steady-state results one simulation at a time:
- #1, a relatively standard dose and interval - 3.3 mg/kg q8H
- #2, dose is 0.0, interval is q8H
- #3, dose is 0.00, interval is q8H
- #4, dose is 0.00, interval is q8H
- Gentamicin pharmacodynamics and target concentrations are not thought to be different in foals than in adult horses. For efficacy, Cmax concentrations of 10 µg/ml or higher are preferred. For safety, Cmin concentrations must fall below 1.0 µg/ml.
Manipulate the dosage
- Step 1: Inspect initial settings and reveal all simulations.
- One by one (to reveal the plots one by one), set the dosage for simulations #2, #3, and #4 to 3.3 mg/kg.
- Step 2:
- Change doses to 9.9 mg/kg for simulations #2, #3, #4
- Change intervals to 24 hours for simulations #2, #3, #4
- Step 1: Changes in λz and T1/2 with declining renal function remain proportional to Clt
- Step 2: λz and T1/2 do not change when dosage is altered. The model remains "dose independent."
Steady-State Concentrations (for repeated doses during therapy).
- Step 1: Changes in Cave with declining renal function remain proportional to Clt. Changes in Cmax and Cmin increase with declining Clt. Cmax increases proportionally less than does Cave. Cmin increases proportionally more than does Cave.
- Step 2: Steady state Cmax approaches or exceeds target maximum concentration ("Upper"). Steady state Cmin approaches or is well below target Cmin for simulations #1, #2 and #3. Steady state Cmin is unacceptably high for simulation #4
- Step 1: Note the increasing concentrations as renal function declines. Note that accumulation does not occur for simulation #1 but becomes apparent as renal function declines.
- Step 2: Note the relationship between plasma concentrations and the targets. Also note that accumulation is still apparent for simulation #2
- The model described in this exercise was dose independent.
- Not all animals could safely be treated with q24H dosing. Longer intervals are advised.
- Animals with levels of renal dysfunction below clinical thresholds for detection can safely be treated with q24H dosing.