Because of these changes in valproate clearance, monitoring of antiepileptic concentrations should be intensified whenever concomitant antiepileptics are introduced or withdrawn. Children within the first 2 months of life have a markedly decreased ability to eliminate valproate compared to older children and adults. Over the age of 10 years, children have pharmacokinetic parameters that approximate those of adults. Accordingly, the initial dosage should be reduced in the elderly. The effects of race on the kinetics of valproate have not been studied.
Liver disease impairs the capacity to eliminate valproate.
Accordingly, monitoring of total concentrations may be misleading since free concentrations may be substantially elevated in patients with hepatic disease whereas total concentrations may appear to be normal. Therefore, no dosage adjustment appears to be necessary in patients with renal failure. The relationship between plasma concentration and clinical response is not well documented. One contributing factor is the nonlinear, concentration dependent protein binding of valproate which affects the clearance of the drug. Thus, monitoring of total serum valproate cannot provide a reliable index of the bioactive valproate species.