Intravenous topiramate: Comparison of pharmacokinetics and safety with the oral formulation in healthy volunteers

Abstract

SUMMARYPurpose: Although oral topiramate (TPM) products are widely prescribed for migraines and epilepsy, injectable TPM is not available for human use. We have developed a solubilized TPM formulation using a cyclodextrin matrix, Captisol with the long-term goal of evaluating its safety and efficacy in neonatal seizures. This study in healthy adult volunteers was performed as required by the U.S. Food and Drug Administration (FDA) to demonstrate the pharmacokinetics and safety prior to initiation of studies involving children. This study allowed investigation of absolute bioavailability, absolute clearance, and distribution volume of TPM, information that could not be obtained without using an intravenous TPM formulation. Methods: This study was an open-label, two-way crossover of oral and intravenous TPM in 12 healthy adult volunteers. Initially two subjects received 50 mg, intravenously and orally. Following evidence of safety in the first two subjects, 10 individuals received 100 mg doses of intravenous and oral TPM randomly sequenced 2 weeks apart. Blood samples were taken just prior to drug administration and at intervals up to 120 h afterwards. TPM was measured using a validated liquid chromatography-mass spectrometry method. Concentration-time data were analyzed using a noncompartmental approach with WinNonlin 5.2.Key Findings: All subjects completed the study. The mean (AEstandard deviation) absolute oral bioavailability was 109% (AE10.8%). For intravenous and oral TPM the mean distribution volumes were 1.06 L/kg (AE0.29) and 0.94 L/ kg (AE0.24). Clearances were 1.33 L/h (AE0.26) and 1.22 L/h (AE0.26). The half-life values were 42.3 h (AE6.2) and 41.2 h (AE7.5). No changes in heart rate, blood pressure, electrocardiography, or infusion site reactions were observed. Mild central nervous system cognitive adverse events and ataxia occurred between dosing and 2 h post dose with both intravenous and oral administration. With intravenous TPM, these adverse effects occurred as early as during the 15-min intravenous infusion. Significance: In healthy adults, oral TPM is bioequivalent to intravenous TPM, and infusion of 50-100 mg over 15 min is safe. Neurologic effects occurred during the infusion, demonstrating that TPM rapidly diffuses into the brain, which supports its evaluation for neonatal seizures. Results from this pilot study will inform the design of subsequent studies in children and newborns, including controlled clinical trials intended to assess the efficacy and safety of intravenous TPM for neonatal seizures. In addition, our results provide support for the further development of intravenous TPM as bridge therapy for older children and adults in whom oral TPM therapy is interrupted.

Advances in Management of Neonatal Seizures

“…The promulgation of topiramate in neonates has been met with two significant challenges: First, to date no intravenous formulation is commercially available, precluding use in patients who are unable to tolerate oral medications. Promising pilot data has demonstrated safety of an experimental intravenous form in adults [30], however neonatal data is lacking. Second, there is significant concern that topiramate adversely affects language development, even in healthy volunteers.…”

A Phase 1c Trial Comparing the Efficacy and Safety of a New Aqueous Formulation of Alphaxalone With Propofol

“…This difference occurred even though the same depth and duration of cortical depression was present in both treatment groups evidenced by the same BIS values shown in Figure 3. The maximum decreases in systolic blood pressure, median (IQR), were 12 (11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22) mm Hg for PHAX and 25 (17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28) mm Hg for propofol and diastolic blood pressure were 14 (9-16) mm Hg for PHAX and 26 (22)(23)(24)(25)(26)(27)(28)(29)(30) mm Hg for propofol. Further, these differences in pressure occurred when the heart rate increases after administration of anesthetic injection, median (IQR) were: 21 (16-24) beats/minute for PHAX and 15 (11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)…”

“…[23][24][25][26][27] It has not been previously investigated as an excipient for alphaxalone. Such a preparation, alphaxalone in aqueous solution with SBECD, Phaxan™ (PHAX), has been made and tested in preclinical studies.…”

Intramuscular and rectal therapies of acute seizures

“…An injectable topiramate (TPM) formulation consisting of 10 mg/mL TPM dissolved in 10% sulfobutyl cyclodextrin has been formulated [41,42]. A commercial formulation is under development.…”