Free Anticonvulsant Concentrations in Patients with AIDS

Seizures are a common manifestation of central nervous system disease in patients with HIV infection. The incidence is approximately 10% in a population of hospitalized patients with an advanced stage of disease (83). Phenytoin is widely prescribed in the treatment of tonic-clonic seizures and other forms of epilepsy. Burger et al. investigated serum concentrations of phenytoin in 21 patients with AIDS. The total phenytoin concentrations were significantly lower in patients with AIDS than in the control population, although phenytoin doses were significantly higher in patients with AIDS. Calculation of Michaelis-Menten parameters demonstrated that Vmax values were similar in patients with AIDS and the control group, but a non-significant trend of lower Km values was observed in patients with HIV. The authors demonstrated that unbound phenytoin concentrations were significantly higher in patients with HIV and concluded that the lower protein binding of phenytoin in patients with AIDS could be related to hypoalbuminemia. Because unbound phenytoin is the pharmacologically active fraction, authors recommended monitoring unbound phenytoin concentrations for patients with HIV infection receiving phenytoin (84). In vitro experiments also confirmed the findings of Burger et al. Concentrations of free phenytoin and free valproic acid were significantly elevated in serum pools prepared from patients with AIDS and supplemented with phenytoin or valproic acid compared with serum pools prepared from normal subjects and also supplemented with the same amount of phenytoin or valproic acid. Hypoalbuminemia alone did not explain the elevation of free phenytoin or free valproic acid. Drug-drug interactions probably play a major role because an average patient with AIDS is receiving more than 10 medications per day (85). Toler et al. (86) also described severe phenytoin toxicity because of decreased protein binding of phenytoin in a patient with AIDS leading to an elevated free phenytoin concentration of 4.9 ^g/mL.

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