Study of antiepileptic drug fosphenytoin; a prodrug of phenytoin prodrug fosphenytoin

Fosphenytoin, the disodium phosphate ester of 3‒ hydroxymethyl‒5,5‒diphenylhydantoin (FPHT/ACC 9653/Cerebyx), phosphate ester pro‒drug of phenytoin, 5,5‒diphenylhydantoin (PHT/ Dilantin), was developed to overcome complications associated with parenteral PHT administration in treatment of seizures, short‒term prophylaxis and treatment of repetitive or prolonged seizures and status epilepticus (SE). Effect of pharmacokinetics, dynamics, clinical efficacy and tolerability of FPHT in children and adults studied. The intravenous (i.m.) FPHT has a similar adverse effect profile than PHT.1 The effect of FPHT, single or adjunctive antiepileptic (AE) in SE, intraperitoneal (i.p.) therapeutically 5 min after seizure onset, only the highest FPHT dose (180 mg/kg) was capable of terminating seizure activity in 50% of the tested animals. FPHT (18‒180 mg/ kg) was administered as a pretreatment, i.p., seizures were blocked in a dose‒dependent fashion. Combinations of diazepam and FPHT were also effective. FPHT (18‒56 mg/kg), given in conjunction with a diazepam (4.8 mg/kg, i.m.) 5 min after seizure onset, enhanced the AE effect of diazepam. When FPHT (18 or 32 mg/kg, i.p.) was given as a pretreatment and diazepam was given 5 min after seizure onset, the 32 mg/kg dose of FPHT significantly reduced the time for seizure control. The FPHT, either alone or in combination with diazepam, has little or no therapeutic AE effects for nerve agent‒induced SE.2 Single intramuscular (I.M) injection of FPHT prevents seizures. FPHT (20 PHT equivalents/kg) examined the prevalence and frequency of clinical seizures. A single i.m injection of FPHT (20 PHT equivalents/ kg) does not prevent seizures or neurologic deficits in childhood acute nontraumatic coma.3 Oral PHT, I.V. PHT, and I.V FPHT are all commonly used for loading PHT in the emergency department.4 PHT is a first‒line drug in the treatment of SE. The parenteral PHT formulation is associated with administration difficulties and therefore FPHT, has been developed. PHT and FPHT were administered by i.v. infusion and blood, cerebrospinal fluid (CSF) and microdialysate samples. The pharmacokinetic parameters in plasma of PHT after PHT and FPHT (30 and 60 mg/kg) administration were indistinguishable. The PHT plasma free fraction was 0.25‒0.31 and 0.26‒0.31 for PHT and FPHT, respectively. Cmax values increased dose‒dependently and were independent of whether PHT or FPHT was administered. The kinetic profiles of PHT for the frontal cortex and hippocampus were indistinguishable suggesting that PHT distribution in the brain is not brain region specific. Thus, overall, the central and peripheral kinetics of PHT are indistinguishable after PHT and FPHT.5 The SE is common in children with severe falciparum malaria and is associated with poor outcome. PHT is often used to control SE, but its water‒ soluble prodrug, FPHT, may be more useful as it is easier to administer. The pharmacokinetics and clinical effects of PHT and FPHT sodium in children with severe falciparum malaria and SE, PHT and FPHT administration at the currently recommended doses achieve plasma unbound PHT concentrations within the therapeutic range with few cardiovascular effects. Administration of FPHT i.v. or i.m. offers a convenient alternative to i.m. PHT.6 Several AEDs are therapeutic in mania and since acute mania requires rapid and intensive treatment, i.v. high‒dose PHT might be acutely antimanic. A prodrug of PHT, FPHT, which has few cardiac or local vein side effects, was also used and no antimanic effects were observed. The i.v. FPHT at doses that are effective in SE appears to be ineffective in acute mania.7