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)
The original dose recommendations for chloramphenicol administration in cats were the same as dogs (50 mg/kg, q8H). Given in this fashion, chloramphenicol produced a greater incidence of side effects (depressed white cell count, anorexia, etc.) in cats than dogs. The recommended cat dosage was subsequently revised to 13 - 20 mg/kg q12H.
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 either species.
- 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: Alter the dosage for cats
- Set the dose to 20 mg/kg.
- Set the weight to any reasonable cat weight. (You don't necessarily need to change this value).
- Set the interval to 12.
Step 1 & 2:
- 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).
- The steady-state Cmax value is lower for cats (using dog dosage) than for dogs. Higher incidence of toxicity in cates would not appear to be related to Cmax.
- Cave and Cmin values are much higher for cats 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
- Plasma concentrations in dogs exceed the upper end of the therapeutic range after each dose is given and fall well below the therapeutic range at the end of each dose interval.
- Plasma concentrations exceed the low end of the therapeutic range and stabilize somewhere near the middle of the therapeutic range. Peak concentrations 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 mcg/ml.
- For the cat simulation, concentrations are below the therapeutic range for much of the dose interval.
- 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.