Phenytoin Prodrug: Preclinical and Clinical Studies

Summary: The currently available phenytoin (PHT) solution has many disadvantages stemming from poor aqueous solubility of PHT. A novel approach to solve the problem has been the synthesis of a phosphate ester of PHT (PHT prodrug ACC‐9653). This water‐soluble compound is metabolized rapidly into P04 and PHT. A four center open‐label, baseline‐controlled study of 43 patients with epilepsy maintained on oral twice‐daily PHT monotherapy was performed to evaluate the safety and pharmacokinetic profile of the prodrug. Patients received an i.v. or i.m. dose of ACC‐9653 at a dose equivalent to the patients' morning dose of PHT. Intravenous dosages were infused at a rate of 75 mg/min, and i.m. dosages were given as one or two injections. After a period of 6 days, during which patients were again maintained with oral PHT, they were given a dose of ACC‐9653 via whichever route they had not yet received. The T_msx of the prodrug averaged 5.7 and 36 min (0.095 and 0.606 h) after i.v. and i.m. administrations, respectively. The elimination half‐life of ACC‐9653 (conversion from prodrug to PHT) after i.v. and i.m. administration was 8.4 and 32.7 min (0.140 and 0.545 h), respectively, and both were independent of the dose. The plasma clearance of ACC‐9653 was not dependent on dose or route of administration and averaged 19.8 ± 1.16 and 17.8 ± 0.83 L/h after i.v. and i.m. administrations, respectively. The area under curve ratio of PHT after i.m. and i.v. ACC‐9653 was 1.17 ± 0.13 which was not significantly different from 1. These findings indicate that both i.v. and i.m. administrations of ACC‐9653 maintained stable levels of PHT. Unlike i.v. PHT infusion, serious cardiovascular and respiratory adverse reactions were not observed during the administration of i.v. ACC‐9653. Postural hypotension was reported in two patients. Paresthesia was the most frequent adverse experience reported during the i.v. infusion of ACC‐9653. The tingling sensation was transient and localized to the groin, lower back, abdomen, head and neck regions. Phlebitis, tissue necrosis, induration, cording and sclerosis were not observed in this patient population following either i.m. or i.v. ACC‐9653 administration. In summary, PHT plasma levels in patients with epilepsy who were receiving chronic oral PHT monotherapy were maintained by the i.m. or i.v. administration of ACC‐9653. Both i.v. and i.m. ACC‐9653 were well tolerated by the patients as evidenced by the absence of serious cardiovascular events, laboratory variable abnormalities, or adverse experiences.