1. Anticonvulsants: Valproic acid

2. Valproic acid
Valproic acid is an agent that is chemically related to free fatty acids and is used in the treatment of generalized, partial, and absence (petit mal) seizures
Valproic acid can be used for the acute treatment and chronic prophylaxis of seizures
Valproic acid is also a useful agent for the treatment of bipolar affective disorders and the prevention of migraine headaches

3. Therapeutic And Toxic Concentrations
The generally accepted therapeutic range for total valproic acid steady-state concentrations is 50–100 μg/mL
Valproic acid is highly protein bound to albumin with typical values of 90–95%
Plasma protein binding of valproic acid is saturable within the therapeutic range, which results in less protein binding and higher unbound fraction of drug at higher concentrations

4. Therapeutic And Toxic Concentrations
The concentration-dependent protein binding of valproic acid causes the drug to follow nonlinear pharmacokinetics (Figure)
This type of nonlinear pharmacokinetics is fundamentally different than that observed during phenytoin administration
Phenytoin hepatic metabolism becomes saturated, which causes Michaelis-Menten pharmacokinetics to take place

5. Therapeutic And Toxic Concentrations
As a result, when phenytoin doses are increased, total and unbound steady-state concentrations increase more than a proportional amount (e.g., when the dose is doubled, serum concentrations may increase three- to five-fold or more)
In the case of valproic acid, when the dose is increased total drug steady-state concentration increases less than expected

6. Michaelis-Menten elimination (e.g. Phenytoin)
Nonlinear vs. Linear
Michaelis-Menten elimination (e.g. Phenytoin)
Saturable plasma protein binding (e.g. Valproic acid) or Autoinduction (e.g. Carbamazepine)

7. Therapeutic And Toxic Concentrations
Unbound steady-state valproic acid concentration increases in a proportional fashion (e.g., when the dose is doubled, total serum concentration increases 1.6–1.9 times but unbound steady-state serum concentration doubles; Figure )

8. Total vs. free drug Total valproic acid concentration
Unbound or free valproic acid concentration

9. Clinical Monitoring Parameters
Patients should be monitored for:
Concentration-related side effects (ataxia, sedation, lethargy, tiredness, tremor, stupor, coma, and thrombocytopenia)
Gastrointestinal upset associated with local irritation of gastric mucosa (nausea, vomiting, anorexia)
Elevated liver function tests, increased serum ammonia, alopecia, and weight gain

10. Clinical Monitoring Parameters
Valproic acid serum concentrations should be measured in most patients
Because epilepsy is an episodic disease state, patients do not experience seizures on a continuous basis. Thus, during dosage titration it is difficult to tell if the patient is responding to drug therapy or simply is not experiencing any abnormal central nervous system discharges at that time

11. Clinical Monitoring Parameters
Valproic acid serum concentrations are also valuable tools to avoid adverse drug effects
Patients are more likely to accept drug therapy if adverse reactions are held to the absolute minimum.

12. Valproic acid clearance
Adults with normal liver function: 9.5 mL/h/kg
Adults with normal liver function receiving other antiepileptic drugs that are enzyme inducers (phenytoin, phenobarbital, carbamazepine): 16.5 mL/h/kg
Valproic acid clearance in patients with liver disease (i.e. cirrhosis) is 3.5 mL/h/kg

13. Valproic acid clearance
Children 6–12 years old with normal liver function: 15 mL/h/kg
Children 6–12 years old with normal liver function receiving other antiepileptic drugs that are enzme inducers (phenytoin, phenobarbital, carbamazepine): 25 mL/h/kg

14. Valproic acid volume of distribution
Valproic acid volume of distribution (V) is 0.15 in adults and 0.2 L/kg in children

15. Initial Dosage Determination Methods
When given by intravenous injection or orally, valproic acid follows a one compartment pharmacokinetic model
When oral therapy is required, valproic acid has good bioavailability (F= 1 for oral rapid-release products, F = 0.9 for oral sustained-release tablets)
Dosing interval between 8–12 hours steady-state serum concentration

16. Initial Dosage Determination Methods

17. Example 1
KL is a 51-year-old, 75-kg (5 ft 10 in) male with tonic-clonic seizures who requires therapy with oral valproic acid. He has normal liver function and takes no medications that induce hepatic enzymes. Suggest an initial valproic acid dosage regimen designed to achieve a steady-state valproic acid concentration equal to 50 μg/mL.

18. Use Of Valproic Acid Serum Concentrations To Alter Doses
Pseudolinear Pharmacokinetics Method

19. Pseudolinear Pharmacokinetics Method
Assume linear pharmacokinetics, then subtract 10–20% for a dosage increase or add 10–20% for a dosage decrease to account for nonlinear, concentration-dependent plasma protein binding pharmacokinetics:

20. Example 2
KL is a 51-year-old, 75-kg (5 ft 10 in) male with tonic-clonic seizures who requires therapy with oral valproic acid. After dosage titration, the patient was prescribed 500 mg every 12 hours of enteric-coated divalproex sodium tablets (1000 mg/d) for 1 month, and the steady-state valproic acid total concentration equals 38 μg/mL. Suggest a valproic acid dosage regimen designed to achieve a steady-state valproic acid concentration of 80 μg/mL.

21. Example 2 (solution)
Using pseudolinear pharmacokinetics, the resulting total steady-state valproic acid serum concentration would equal
The dose was rounded to 2000 mg/d or 1000 mg every 12 hours

22. Example 2 (solution)
Because of nonlinear, concentration-dependent protein binding pharmacokinetics, the total steady-state serum concentration would be expected to be 10% less, or 0.90 times, to 20% less, or 0.80 times, than that predicted by linear pharmacokinetics:
Css = 80 μg/mL ⋅ 0.90 = 72 μg/mL and
Css = 80 μg/mL ⋅ 0.80 = 64 μg/mL.
Thus, a dosage rate of 2000 mg/d would be expected to yield a total valproic acid steady-state serum concentration between 64–72 μg/mL.