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 which gentamicin will no longer be effective.
Experts have agreed on a target Cmax of at least 10 μg/ml. (The value of upper on the worksheet).
Aminoglycoside toxicity is associated with "elevated" Cmin (the value of "lower" on the worksheet) 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 - Inspect
Step 1. Change the dose to 9 mg/kg and the dose interval to 24 hours for simulations #2 and #4.
Calculated values - changing the dose and interval did not change T1/2 and λz Steady-State Concentrations - 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. 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).
Calculated values - A 50% reduction of clearance increased T1/2 and reduced λz proportionally. Steady-State Concentrations - 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. 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).
Calculated values - T1/2 and λz changed, proportional to the change in Clt. Steady-State Concentrations - Cmin values are above the "Lower" target for all simulations although the percentage is small and may not be clinically important. Changes in Cmax are nominal for all simulations.
Remember that the graphs run for 24 hours. When half-lives are long (simulations #2 and #4 after adjustments), a single dose graph using this spreadsheet may not represent steady state concentrations. In this case, we can estimate that 97% of steady state is reached within 5 half-lives. 5 x T1/2 for simulation #2 (after step 3, the final reduction in clearance) is 5 x 4.62 hours or 23.1 hours. So in this case, the graph provides a reasonable estimate of Steady-state. Please note, after step 3, there is slight accumulation after the first dose. As renal function declines, this becomes more obvious and more clinically relevant.
The model described in this exercise was dose independent.
Reasonable concentration targets were acheived when 3 mg/kg q8H was given to horses with normal renal function.
Reasonable concentration targets were acheived when 9 mg/kg q24H was given to horses with renal function that appeared "normal" (routine blood work was normal).
Technically, Cmin concentration targets were exceeded when 9 mg/kg q24H is given to horses with 75% loss of renal function. Clinically and practically, 1.16 - 1.26 μg/ml may not be important increases over the 1.0 μg/ml target. HOWEVER, any further decline in renal function