Module 9. Relationship between volume of distribution and clearance. Effect of volume of distribution (only) changes.
Having completed this exercise and based on pharmacokinetic constants and data, students should be able to:
- Describe the general approach to modification of the (published) adult dosage of amikacin when it is used to treat or prevent systemic infections in foals.
S.L. Green et. al.: Effects of hypoxia and azotaemia on the pharmacokinetics of amikacin in neonatal foals. Equine Veterinary J. 24(6), 475-479, 1992.
Gram-negative septicemia in the newborn foal is a major cause of neonatal mortality. Aminoglycoside antibiotics are an excellent choice for treatment or prevention of gram negative sepsis. However, aminoglycoside pharmacokinetics are different in foals than in adult horses. Consequently, it is important to make appropriate dose and interval corrections in order to provide safe and effective therapy. Especially in foals, it is possible to produce aminoglycoside toxicity without producing bactericidal aminoglycoside therapy!
Download amikacinvolume.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 amikacin in horses.
- Simulation #1 is preset for a typical adult horse given amikacin.
- Simulation #2 is preset for a typical foal given amikacin.
- The doses and intervals for both simulations are set as if both simulations are adults.
- "Upper" is set to 30. Reaching this concentration improves amikacin efficacy. There may actually be some advantage to achieving higher concentrations and it appears that higher concentrations do not increase incidence of toxicity.
- "Lower" is set to 3.0. The concentration of amikacin MUST fall below this level to avoid toxicity.
Manipulate the dosage
- Step 1: Initial conditions
- Compare the pharmacokinetics, steady-state plasma concentrations and graphs for adults and foals given adult doses of amikacin.
- Step 2: Increase efficacy
- Adjust the dose setting of simulation #2 (foal) until the maximum plasma concentration (Cmax) rises to at least the level of the adult. (The minimum concentration should now be even higher.)
- Step 3: Increase safety
- Change the interval setting of simulation #2 (foal) to 12 or 24. Repeat step 1 if necessary. The goal is to establish the (calculated) Cmax at roughly 30 μg/ml and Cmin fall to 3.0 or less.
- Step 1: T1/2 is longer in foals than adults even though Clt is the same.
- Step 2&3: Increasing the dose does not change T1/2 or λz. The pharmacokinetics remain independent of the dose.
Steady-State Concentrations (for repeated doses during therapy).
- Step 1:
- Adult Cmax (simulation #1) approach the target "Upper" concentrations. Efficacy for susceptible organisms is likely.
- Foal Cmax (simulation #2) are slightly more than half of the target upper concentration. amikacin may not be effective at these concentrations.
- Step 2:
- Increased foal Cmax concentrations are more likely to produce effective therapy.
- Foal Cmin concentrations are even higher (even more likely to be toxic).
- Step 3:
- Foal Cmax and Cmin concentrations are now similar to adult values (at higher doses and longer intervals).
- Step 1&2: Accumulation occured in this foal when the dose interval was 8 hours.
- Step 3: Aaccumulation no longer occured in this foal when the dose interval wais 24 hours.
- The model described in this exercise was dose independent.
- It appears that foals can be dosed with relative safety and efficacy.
- It is unlikely that the activity profile (efficacy and toxicity) can be made the same
- It should be noted that neonatal foals under intensive care may have less than normal renal function (and clearance of aminoglycosides).
- List the most (clinically) important differences in calculated values between adults and foals.
- What general recommendations can be made for the proper dose and interval of aminoglycosides given to neonatal foals?
- Examine the plot of the plasma concentration profile for the foal after you make your final dose adjustment. The plasma concentrations are below MIC for typical sensitive organisms (2.0 - 3.0 μg/ml) for about 6 hours out of each dose interval. What could you do for this patient to provide continuous antimicrobial therapy without risking gentamicin intoxication? (It should be clear that changing doses and intervals of gentamicin will not work. You need to think outside the pharmacokinetic box.)