Module 6. Clinical implications of various dosing protocols on amikacin safety and efficacy.
Having completed this exercise and based on pharmacokinetic constants and data, students should be able to:
- Describe the concentration versus time profile differences between q8H and q24H dosing of amikacin.
- Explain why, in the absence of drug concentration data, q24H dosing is likey safer than q8H.
R.D. Moore et al: Clinical response to aminoglycoside therapy: Importance of the ratio of peak concentration to minimal inhibitory concentration. J. Infectious Diseases 155(1), 93-99, 1987.
J.D. Baggott et al: Clinical pharmacokinetics of amikacin in dogs. American J of Veterinary Research 46(8), 1793 - 1796, 1985.
Dosage recommendations for amikacin range from 10 mg/kg every 8 hours to 30 mg/kg every 24 hours. At this time, there seems to be a clinician preference for high doses once each day (so-called pulse dosing). The approach is thought to be as efficacious and less toxic (nephrotoxicity is associated with high trough concentrations rather than high peak concentrations). MIC values for susceptible organisms range from 2 to 8 μg/ml. It requires 2 - 3 x MIC to reach minimum bactericidal concentrations (MBC). Some authors refer to Cmax: AUC ratios as these may explain the efficacy of pulse dosing.
Download amikacindosage.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.
The pharmacokinetic variables on the spreadsheet are preset for a typical dog given amikacin. Simulation #1 is set for a dose interval of 8 hours (and the appropriate dose) and simulation #2 is set for a dose interval of 24 hours.
- The lower concentration is set to 3.0 μg/ml. The concentration of amikacin MUST fall below this level to avoid toxicity.
- The upper concentration is set to 30.0 μg/ml. 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.
- You do not need to adjust these values
Manipulate pharmacokinetic parameters
- Step 1. Inspect calculated values, steady state values and the graphs before making any changes.
- Step 2. Change Clt for both simulations to 0.08 l/kg/hr (this represents roughly a 50% reduction in renal function, undetectable using BUN and Creatinine values).
- Step 3. Change Clt for both simulations to 0.04 l/kg/hr (this represents roughly a 75% reduction in renal function).
- Step 1. Note that the model assumes that amikacin pharmacokinetics are dose independent (λz and T1/2 are the same for both dosing schemes). This relationship remains true for all the other simulations (this does not confirm that amikacin pharmacokinetics are in fact dose independent).
- Step 2. Note that λz and T1/2 changed proportionally to the change in clearance.
- Step 3. Note that λz and T1/2 changed proportionally to the change in clearance.
Steady-State Concentrations (for repeated doses during therapy).
- Step 1. Note that Cmax values correlate (direclty and almost exactly) with dose amounts.
- Step 2. Note that Cmin for the q8H dose (#1) is VERY close to the 3.0 μg/ml Cmin target.
- Step 3. Note that Cmin for the q8H dose (#1) clearly exceeds the desired Cmin target. Note that for the q24H dose (#2) concentrations still fall below a Cmin target of 3.0 μg/ml.
- Step 1. The graphs should confirm the steady state values as 5 half-lives have elapsed by the end of the first dose interval for both simulations. Note how long concentrations fall below Cmin for each dose interval and each simulation.
- Step 2. The graph of simulation #1 shows a hint of accumulation (second peak is higher than the first peak). T1/2 is now nearly 2 hours so 5 half-lives have NOT elapsed by the end of the first dose interval. Simulation #2 dose not show evidence of accumulation.
- Step 3. T1/2 is now approximately 4 hours. Simulation #1 shows clear evidence of accumulation prior to reaching steady state. Simulation #2 shows a hint of accumulation between the first and second dose (it's MINIMAL). Note that dosing in simulation #2 still achieves the target concentration goals.
- The model described in this exercise is dose independent.
- Amikacin, administered at 10 mg/kg q8H appeared as if it were:
- probably both effective and safe in normal dogs.
- probably effective but possibly not safe in dogs with 50% loss of renal function.
- probably effective but probably not safe in dogs with 75% loss of renal function.
- Amikacin, administered at 30 mg/kg q24H appears as if it can be:
- probably both effective and safe in normal dogs.
- probably effective and probably safe in dogs with 50% loss of renal function.
- probably effective but possibly not safe in dogs with 75% loss of renal function (and probably not safe if renal function declines further).
- The Cave value is the same for both simulations and at all clearance settings. Why is this so?
- Which regimen is more certain to produce bactericidal concentrations? Remember, you are unlikely to KNOW the MBC for a particular bacterial infection. You are interested in improving the ODDS that the bacteria is exposed to sufficiently high concentrations.
- If you do not know the patient's renal status, which regimen is less likely to result in toxicity?
- Which regimen is more likely allows the plasma concentrations to fall so low that the bacteria start to regrow at the end of each dose interval?