Module 3. Effects of altered clearance on plasma concentrations.
Having completed this exercise and based on pharmacokinetic constants and data, students should be able to:
Describe how once daily dosing of aminoglycosides reduces the toxic potential of aminoglycosides.
Describe limitations of routine bloodwork ([BUN], [creatinine]) for predicting the safety of aminoglycosides.
Describe the effect of a change in total clearance on the fraction of the administered dose remaining at the end of a dose interval.
Describe the effect of a change in total clearance on drug accumulation and steady state concentrations (Cmax, Cave, Cmin) that result from repeated administration.
Describe how reduced clearance affects the maximum concentration achieved following a single dose.
Dysfunction of the organs of elimination (renal failure, hepatic failure, etc.) is associated with reduced clearance. Changes in volumes of distribution are usually small. Reduced total clearance changes the drugs half-life, average concentration and peak and trough concentration. Dosing in such patients should be done with some understanding of the effect of organ failure on the pharmacokinetics of the drug. In the specific case of gentamicin, lower than normal clearance greatly increases the incidence of toxicity.
Download clt.xlsx, the worksheet 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 and doses on the spreadsheet are preset for a typical adult horse given gentamicin according to original (and still often cited) doses and eight hour intervals.
Half-lives of aminoglycoside antibiotics are very short (roughly an hour). Concentrations of these drugs decline very rapidly after they are administered. Traditionally, they have been administered with dose intervals of 6 - 8 hours. Unfortunately, the renal elimination of aminoglycosides is often reduced when renal dysfunction cannot be detected clinically. Current recommendations for dosing aminoglycosides are based on principles that were originally referred to as "pulse dosing." In essence 3 or 4 doses (original dosage) are combined into one daily dose. The practice is so common now that the phrase "pulse dosing" has essentially been abandoned.
Aminoglycoside efficacy is associated with high peak concentrations of the drug. It is also reasonble to assume that there is some Cmax below hich gentamicin will no longer be effective.
Experts have agreed on a target Cmax of at least 10 μg/ml.
Aminoglycoside toxicity is associated with "elevated" Cmin which in turn leads to accumulation in endothelial cells lining renal tubules and semicircular canals. For gentamicin specifically, the Cmin concentration should fall below 1.0 μg/ml.
Manipulate dosage and pharmacokinetic parameters
Step 1. Change the dose to 9 mg/kg and the dose interval to 24 hours for simulations #2 and #4.
Step 2. Change Clt of all simulations to 0.06. This represents a 50% reduction in renal function compared to normal (which you cannot detect by routine blood work).
Step 3. Change Clt of all simulations to 0.03. This represents a 75% reduction in renal function compared to normal (which you can detect using BUN/Creatinine).
Step 1. Changing the dose and interval did not change T1/2 and λz
Step 2. A 50% reduction of clearance reduced T1/2 and λz proportionally.
Step 3. T1/2 and λz changed, proportional to the change in Clt.
Steady-State Concentrations (for repeated doses during therapy).
Step 1. Cmin values are below the "Lower" target for all simulations. Cmax values greatly exceed desired "Upper" target for simulations #2 and #4 after the change in dosage.
Step 2. Cmin values are above the "Lower" target for simulations #1 and #3 (8 hour dose interval) and remain below "Lower" target for #2 and #4. Changes in Cmax are nominal for all simulations.
Step 3. Cmin values are above the "Lower" target for all simulations. Changes in Cmax are nominal for all simulations.
Note that the graphs run for 24 hours. When half-lives are long (simulations #2 and #4 after adjustments), these graphs do NOT represent steady state concentrations.
The model described in this exercise was dose independent.
Reasonable concentration targets were acheived when 3 mg/kg q8H was given to dogs with normal renal function.
Reasonable concentration targets were acheived when 9 mg/kg q24H was given to dogs with renal function that appeared "normal" (routine blood work was normal).
Cmin concentration targets were exceeded when 9 mg/kg q24H is given to dogs with 75% loss of renal function.