Module 4. Effects of altered volume of distribution on plasma concentrations.
Having completed this exercise and based on pharmacokinetic constants and data, students should be able to:
- Describe the general relationship between Vz (volume of distribution), Clt (total clearance), the λz (elimination rate constant) and T1/2 (half-life).
- Describe differences between adults and neonates in terms of the pharmacokinetics of aminoglycoside antibiotics.
- Describe how differences between adults and neonates effect dosing generally.
- Vz may be altered by disease processes (dehydration), physiologic states (neonates), or the addition of a "displacing" (second) drug.
- Altered Vz changes the direct relationship between the amount of drug in the body and the plasma concentration (demonstrated most easily at time=0 following IV administration)
- Altered Vz changes λz without changing Clt. It's reasonable to think that a large Vz requires longer (for livers and kidneys) to process.
Download vz.xlsx, the worksheet for this module. Depending on your settings, you may have to "enable editing" in order to make the changes suggested by the exercise.
Pharmacokinetic variables on the spreadsheet are preset for a typical adult horse (#1) and "typical" neonate (#2) given gentamicin.
- Gentamicin pharmacodynamics and target concentrations are not thought to be different in foals than in adult horses.
- Gentamicin is an efficient bactericidal antibiotic. Antibacterial efficacy of gentamicin is considered to be directly related to Cmax. Above some bactericidal concentration threshold, increasing Cmax concentrations will increase bacterial killing efficiency.
- Somewhat arbitrarily, Cmax concentrations of 10 µg/ml or higher are established as a target Cmax. Higher concentrations are thought to produce greater efficacy.
- Renal and otic toxicity have been clearly linked to low Cmin concentrations. Cmin must fall below 1.0 µg/ml before gentamicin can be safely re-dosed.
- Step 1. Inspect the values "as loaded."
Caculated values - Compare Clt, T1/2, and λz between adult (#1) and foal (#2). When the spreadsheet loads, the difference in these calculated values is caused entirely by the difference in Vz between adults and foals. For adults steady state(5 x T1/2) is reached within the dose interval, accumulation with repeated doses is not significant. For foals steady state is reached after the second dose. Accumulation with repeated doses will be significant.
Steady-State Concentrations - Note that calculated values for Cmax is lower in foals, Cmin is higher and Cave is the same (Cave depends ONLY on clearance and dose rate). The foal values appear to be less than desired for efficacy and greater than desired for avoiding toxicity. If you adjust the dose to increase Cmax (for efficacy), what happens to Cmin?
- Step 2. Change the dose to 9.0 µg/ml and the interval to 24 hours to better reflect current practice (pulse dosing) for gentamicin.
Caculated values - The calculated values do not change with the change in dose and interval. Pharmacokinetics of Gentamicin are portrayed as dose independent in both adults and foals. Accumulation is insignificant for both simulations
Steady-State Concentrations - Cmax in foals now appears to be adequate (though it is still very much lower than Cmax in adults of course). Cmin appears to be safe.
- Plasma concentration vs time profiles are very different. The simulations predict that clinical effects may be different in adults and foals.
- The model described in this exercise was dose independent.
- Plasma concentrations in foals dosed as adults were initially. This raises a concern that efficacy may be reduced in foals. This has not been confirmed clinically.
- Plasma concentrations persisted in foals for a greater portion of the dose interval. Gentamicin was eliminated more slowly. The clinical consequences are not known.
- Estimate a dose of gentamicin would produce a Cmax in foals similar to that of adults dosed at 9.0 mg/kg. Assume a 24 hour dosing interval. (The number need not be exact. You may use the Excel worksheet for this purpose if you wish)
- Any potential for drug accumulation with repeated doses is reduced directly by:
- Decreasing the dose
- Increasing the dose interval
- Defend this statement: "Dosing a foal as if it were an adult creates the risk of producing gentamicin toxicity without efficacy."