Module 5. Species differences in pharmacokinetics (Cats are not small dogs).
Having completed this exercise and based on pharmacokinetic constants and data, students should be able to:
- Explain why it may be difficult (if not impossible) to produce a safe, effective and practical dosage regimen for particular drugs used to treat particular species.
Pharmacokinetic parameters and dosage recommendations are taken from the USP Veterinary Drug Monograph "Chloramphenicol" (http://www.aavpt.org/associations/12658/files/chloramphenicol.pdf)
- Years ago, dose recommendations for chloramphenicol administration in cats were the same as dogs (50 mg/kg, q8H).
- When cats are administered according to the "dog dosage," chloramphenicol produces a greater incidence of side effects (depressed white cell count, anorexia, etc.).
- The recommended cat dosage was subsequently revised to 13 - 20 mg/kg q12H (per USP Monograph).
- Cat dosing recommendations in the USP monograph also include this statement: "Doses of 25 to 50 mg per kg of body weight every twelve hours have been recommended, and may be necessary for some infections, but could increase the risk of side effects".
Download chloramphenicol.xlsx, (the worksheet for this module). Depending on the security setting of your computer, you may have to "enable editing" in order to make the changes suggested by the exercise.
Pharmacokinetic variables for the "Dog" simulation values published for dogs. Pharmacokinetic variables for the "Cat" simulation are values published for cats.
Doses and intervals for both simulations are set to 50 mg/kg q8H (typical dog dosing regimen).
- The therapeutic (safe and effective) concentration range for chloramphenicol (all species?) is 5 - 15 μg/ml. "Lower" is set to 5 and "Upper" to 15 to highlight this range. Assume this range is a valid representation of chloramphenicol efficacy in dogs and cats.
- At some higher (and largely undocumented) concentration, side effects related to inhibition of protein synthesis in the patient occur. The odds that a dose regimen will produce toxicity are greater when higher concentrations are approached.
Manipulate the dosage
Step 1: Before you make changes, review pharmacokinetic variables, calculated values and steady state calculated values.
Step 2: Enter the "recommended" cat dose for simulation #2.
- Set the dose to 20 mg/kg.
- Set the interval to 12.
- Set the weight to any reasonable cat weight. (You don't necessarily need to change this value).
Step 3: Enter the "high" cat dose for simulation #2.
- Set the dose to 50 mg/kg.
- Leave the interval set to 12.
Step 1, 2 & 3:
- Note that the elimination rate constant is much larger in dogs than cats (>4x)
- Note that the T1/2 is much shorter in dogs than cats (<1/4)
Steady-State Concentrations (for repeated doses during therapy).
- Cave and Cmin values are much much higher for cats than for dogs. This may be enough to explain the higher incidence of toxicity.
- The steady-state Cmax value is lower for cats (using dog dosage) than for dogs.
- Steady state concentrations are MUCH lower for the cat regime in cats than for the dog regime in dogs. If this regime is truly safer for cats, this supports the notion that toxicity IS correlated to plasma concentrations (even if Cmax is not the specific measure of toxicity).
- Steady state concentrations are MUCH lower for the cat regime in cats than for the dog regime in dogs. If this regime is truly safer for cats, this supports the notion that toxicity IS correlated to plasma concentrations (even if
- Plasma concentrations in dogs exceed the upper end of the therapeutic range for each dose interval
- Plasma concentrations in dogs fall well below the therapeutic range at the end of each dose interval.
- Plasma concentrations in dogs exceed the Lower limit for approximately 1/2 of each dose interval.
- Plasma concentrations in cats remain above 10 μg/ml throughout dosing.
- Peak plasma concentrations in cats are lower than those achieved in dogs given the same dose at the same interval.
- For the cat simulation, Cmax (peak) concentrations exceed the minimum effective concentration ("Lower") by only 2.7 μg/ml.
- Plasma concentrations in cats are below the therapeutic range for more than half of each dose interval.
- For the cat simulation, Cmax (peak) concentrations exceed the toxic concentration for a portion of each dose interval.
- Cmax is still lower in cats than in dogs
- Plasma concentrations in cats (almost) remain in the therapeutic throughout dosing.
- Based on the initial conditions (cats dosed with dog doses) the higher incidence of toxicity in cats would not appear to be directly related to high Cmax
- Cave and Cmin are higher than in dogs
- Cats may be more sensitive to toxic effects of chloramphenicol than dogs, but the difference is likely based on pharmacokinetics.
- The model described in this exercise is dose independent.
- When the pharmacokinetics of a drug are very different in different species, it may not be possible to produce the same clinical response in the those species.
- For antimicrobials, efficacy is an affect on bacteria and toxicity is an effect on patients. Concentrations required for efficacy are likely the same between two (patient) species. Concentrations that produce toxicity may be different between them.
- Efficacy of the 20 mg/kg q12H regimen appeared doubtful because the time above minimum effective concentrations appeared to be inadequate.
- Based on the information presented in this module does it appear that chloramphenicol can be given to cats in a way that is as effective, as safe and as practical as it is given to dogs?
- This quote appears in cat "usual dose" section(s) of the USP monograph for Chloramphenicol: "Doses of 25 to 50 mg per kg of
body weight every twelve hours have been recommended, and may be necessary for some infections, but could increase the risk of side effects". In terms of the plasma concentration vs time profile, why might 50 mg/kg be a more effective dose?
- Based on the same USP quote in question 2 and in terms of the plasma concentration vs time profile, why might 50 mg/kg be a more toxic dose?