Module 2. Effects of dose rate and dose interval on plasma concentrations.
Having completed this exercise and based on pharmacokinetic constants and data, students should be able to:
- Describe how Cmax (aka peak), Cave (aka average) and Cmin (aka trough) relate to the drug effects seen in patients.
- Compare two dose regimens (for the same drug) and predict which will produce higher or lower Cmax, Cave and Cmin plasma concentrations.
- Describe manipulations of doses and intervals to affect a change in Cmax, Cmin, and Cave plasma concentrations.
Frequently, dose recommendations in the literature are specified as ranges of both dose and interval. (Kirk Current Veterinary Therapy XI lists a dosage for phenobarbital of 0.5 - 3.0 mg/kg q8 - 12H PO). Although some of this range is necessary to make dosing practical (there are a limited number of tablet sizes available), not all doses and intervals produce the same effect and/or toxicity. It is important to understand the effect of changing dose rate and dose and interval.
- Average concentrations are most important for phenobarbital. Phenobarbital has a (very long) half-life of 60 hours and a (comparatively short) 12 hour dosing interval. As a consequence differences between Cmax and Cmin are not great. Efficacy is a matter of producing stable concentrations in the CNS and the major toxicity of phenobarbital (liver failure) is related to chronic therapy. It may be that an excessively high Cmax is related to drug-induced depression (sleepiness) in some patients, but in general Cave is the most important for phenobarbital.
- By way of contrast, gentamicin is a drug for which Cave is NOT especially important. Cmax and Cmin are critical for gentamicin therapy. (This is demonstrated in other Kineticlass modules). A high Cmax is preferred for antimicrobial effect and, for clinically relevant doses anyway, not directly associated with the most common toxic effect(s) of gentamicin. On the other hand, the Cmin of gentamicin MUST fall below a particular target concentration to avoid accumulation in cells lining renal tubules and semi-circular canals of the ear.
Download doserate.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 worksheet are preset for a typical adult dog given an phenobarbital. Please note, the dose and interval were chosen for the purposes of this exercise and are not the only appropriate dose regimen for dogs.
- The upper and lower concentrations set for this exercise indicate the suggested therapeutic range (of effective concentrations) for phenobarbital. This concentration range brackets concentrations that have been noted as efficacious for dogs. You should think that an average concentration in this range MAY BE effective for any given dog. Dosing to produce an average concentration somewhere in the effective range does NOT guarantee efficacy in a particular dog. You do not need to change these values for this exercise.
- Step 1: When the spreadsheet opens, doses and intervals are set to produce steady-state concentrations that are between the lower and middle 1/3 of the therapeutic range for a "typical" seizure patient. The three simulations overlap.
- Step 2: Assume that this dog and owner return after a month of therapy and the dog continues to have 2 seizures each day.
- You and the owner agree that the seizures are not adequately controlled.
- Increase the dose for simulation #2 to 3.6 mg/kg. (and send the dog home)
- Step 3: Assume that two weeks later, the dog and the owner return. The dog has only had two seizures this past week but the owner reports that for the first two days the dog seemed "dazed and confused" for several hours after dosing, but now seems normal.
- You and the owner agree that seizure control is nearing your goal.
- You conclude that the rise change in average phenobarbital concentration.
- You decide that next time you would consider an alternate way to increase the daily dose of phenobarbital by 50%. If you shorten the dose interval by 50% you get the same increase in DOSE RATE as increasing the dose by 50%.
- Decrease the dose interval for simulation #3 to 8 (hours). Do not change the dose.
- Calculate the dose rate for each simulation (after you made the changes). Simulations #2 and #3 each represent a 50% increase in dose rate compared to simulation #1.
- Note that the calculated values do not change when you change the dose. For this exercise at least, phenobarbital is considered to have dose-independent pharmacokinetics.
Steady-State Concentrations (for repeated doses during therapy).
- Compare Cmax, Cave and Cmin within each simulation.
- Compare Cave values among the three simulations. Cave for simulations #2 and #3 reflects the 50% increase in the dose rate when compared to simulation #1.
- Compare Cmax and Cmin between simulations #1 and #2. These concentrations directly reflect the 50% increase in the dose rate.
- Compare Cmax and Cmin between simulations #2 and #3. Simulation #3 (lower dose / shorter interval) should have lower Cmax and higher Cmin than simulation #2.
- Differences between so-called peak and trough concentrations are not large (and perhaps not meaningful) for phenobarbital. Most dogs experiencing mild sedation when first treated with phenobarbital will quickly develop tolerance to this effect.
- Note that the graphs display only the first 4-6 dose intervals.
- Phenobarbital will continue to accumulate (significantly) until at least 5 half-lives have elapsed. At what time will 97% of steady-state be reached?
- Compare the curves for simulations #2 (dashed line) and #3 (red line). Despite the difference in interval, repeated dosage causes the Cave (the average of each individual dose curve) to increase at the same rate. This is visual evidence that fractional accumulation and the approach to steady-state do not depend on the dose rate. Things may be very different for a drug with a short half-life.
- The model described in this exercise was dose independent.
- Large doses and long intervals produce high peaks and low troughs.
- Small doses and short intervals produce lower peaks and higher troughs.
- The average concentration is controlled the dose rate (dose divided by interval). Different regimens can produce the same average.
- The significance of these facts depends on the drug (Does the regimen produce a toxic peak? and ineffective trough? an effective average?)
- For a drug with an extremely long half-life such as phenobarbital, there may be very little (or no) advantage to q8H vs q12H (at the same RATE)
- Which is true?
- Cave for 5 mg/kg q12H is less than Cave for 5 mg/kg q8H
- Cave for 5 mg/kg q12H is greater than Cave for 5 mg/kg q8H
- Cave for 5 mg/kg q12H equal to Cave for 5 mg/kg q8H
- Which dosage would double Cave of a 2 mg/kg q12H dosage regimen?
- 2 mg/kg q6H
- 4 mg/kg q24H
- These dosages would produce the same Cave. Which dosage would have a higher Cmax?
- 2 mg/kg q12H
- 4 mg/kg q24H
- Based on the worksheet values for this module, show calculations for an intravenous dose to produce the same Cave as that calculated for simulation #2 at the end of the exercise.