Module 8. Effect of chronic phenobarbital administration on phenobarbital pharmacokinetics (hepatic enzyme induction and hepatic failure).
Having completed this exercise and based on pharmacokinetic constants and data, students should be able to:
Describe changes in the relationship between dosage and serum concentrations that will occur if a drug induces the enzymes responsible for its metabolism.
Describe changes in the relationship between dosage and serum concentrations that will occur as a primary organ of elimination fails.
W.R. Ravis, et al: Pharmacokinetics of phenobarbital in dogs given multiple doses. American J. Veterinary Research, 50(8), 1343 - 1347, 1989.
Phenobarbital is given chronically to dogs in order to control epileptic seizures. As time passes, phenobarbital increases hepatic enzymes (induction) to produce an increase in the clearance of phenobarbital itself. Veterinarians should expect that multiple dose rate adjustments will be required in order to maintain relatively constant plasma concentrations of phenobarbital. Hepatic disease or drug interactions may also reduce the efficiency of elimination of the phenobarbital.
Download hepaticenzymes.xlsx, the spreadsheet for this exercise. 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 dog that has received phenobarbital for 2 weeks (Simulation #1) and that same dog after receiving phenobarbital for 90 days (Simulation #2). Also note the slight effect of enzyme induction on the fraction of an oral dose that's absorbed (F is lower).
When the spreadsheet loads the upper and lower concentrations are set to the upper (40 μg/ml) and lower (10 μg/ml) concentrations of the published "therapeutic concentration range" for phenobarbital. The published therapeutic range simply means that "some dog somewhere responded to some concentration in this range". It does NOT mean that a particular patient will have seizures controlled at ANY concentration in the range.
Step 1: Acknowledge an "individualized" therapeutic range. Assume that in order to control this dogs seizures initially, you determined that an average concentration in the upper 1/3 of the therapeutic range (35 μg/ml) was necessary. Adjust the lower concentration to reflect this information (set lower = 30 μg/ml).
Step 2: Adjust dose to compensate for hepatic enzyme induction (and regain seizure control). Increase the dose for simulation #2 to produce serum concentrations that will once again control this dog's seizures. You can either do this in a stepwise (estimation) fashion or recognize that clearance has increased by 50% and the dose must be increased by the same portion (new setting 3.6 μg/ml).
Step 3: Adjust pharmacokinetics to reflect hepatic failure. Decrease Clt for simulation #2 to 0.0022 to represent a 50% loss in efficiency of the hepatic enzymes. Slightly more of each dose will be absorbed than either previous state. Increase F to 0.85
Step 4: Adjust dosage to compensate for reduced hepatic function. Clearance (hepatic failure) is 1/3 of the previous (induced) value. Reduce the dose to 1/3 of the previous dose (1.2 mg/kg).
Step 1: Compare the two simulations. A higher Clt (simulation #2) alters λz and T1/2. The change of the "Lower" target concentration is consistent with the fact that epileptic seizures will no longer be controlled in certain patients because their steady state concentrations are lower than they once were.
Step 2: These calculated values do not change with a change in dosage.
Step 3. Note the exceptionally high concentrations produced. Remember that failure will likely occur later than induction. You may have increased the dose rate of phenobarbital several times in response to increasing clearance (induction) and now you have to go the other way.
Step 4. These calculated values do not change with a change in dosage.
Steady-State Concentrations (for repeated doses during therapy).
Step 1: Cmax, Cave and Cmin are decreased proportional to the increase in Clt (caused by enzyme induction). Changing the therapeutic range had no effect.
Step 2: Cmax is slightly higher for simulation #2 under these new conditions. Cave and Cmin are nearly identical to the initial state.
Step 3: All values for simulation #2 are much higher than simulation #1 (the initial state).
Step 4: Cmax, Cave and Cmin should be within the therapeutic range for THIS DOG.
Step 1: Compare simulations #1 and #2. Based on your knowledge of concentrations required to maintain seizure control in THIS dog, what change would you expect in seizure control between #1 and #2 (same dog and dosage after 90 days)?
Step 2: Note that the graphs reflect the new steady-state values and concentrations remain within this patients individualized therapeutic range.
Step 3: Compare simulations #1 and #2. Based on your knowledge of effects of phenobarbital (in addition to hepatotoxicity), what clinical signs would you expect for concentrations you see for simulation #2.
Step 4: The concentration values should have returned to the individualized concentration range. You may be able to adjust the dosage a bit more, but you cannot reasonably expect the two plots to superimpose.
The model described in this exercise was dose independent. Changes in dosage (alone) did not change pharmacokinetic parameters.
Hepatic enzyme induction and subsequent increases in clearance appeared to reduce likely efficacy.
Both clearance and absorption (F) of phenobarbital were affected by changes in hepatic clearance.
Dosage adjustments may be required throughout (lifelong) phenobarbital therapy for control of epileptic seizures.