Topiramate (TPM), available as tablets and sprinkle capsules, is approved for use in adults for prophylaxis of migraines and for patients ages 2 and older with epilepsy. There is, however, no available intravenous product. We have established a program to develop an injectable TPM formulation to evaluate its treatment in hypoxic-ischemic brain injury in newborns. This report deals with the first study comparing oral and intravenous TPM in volunteers as an early step in this process.
Topiramate has a broad range of pharmacologic effects. TPM blocks voltage-gated sodium channels, augments γ-aminobutyric acid (GABA) at certain subtypes of GABAA receptors, inhibits α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) and kainate glutamate ionotropic receptors, and is a weak inhibitor of some isoenzymes of carbonic anhydrase (CA-II and CA-IV; Sachdeo, 1998). However, the precise mechanisms by which it exerts its antiseizure effect has not been determined. An important recent finding is that TPM is highly effective in controlling seizures and is neuroprotective in newborn laboratory animal models of status epilepticus and cerebral ischemia (Yang et al., 1998; Niebauer & Gruenthal, 1999; Lee et al., 2000; Cha et al., 2002; Follett et al., 2004; Koh et al., 2004).
Hypoxic-ischemic brain injury in newborns is a significant medical problem with a high mortality rate; grave neurologic sequelae including impaired cognition and neonatal seizures; and serious treatment-related adverse effects. All of these can cause further brain injury leading to significant morbidity in later life.
The drugs of choice to treat neonatal seizures are phenobarbital and phenytoin. However, <50% of newborns respond to therapy with these medications and both are associated with serious adverse effects including further brain injury, acute systemic toxicity, and significant drug interactions (Painter et al., 1999; Bittigau et al., 2003; Glier et al., 2004). A safer, more effective treatment for neonatal seizures combined with the potential for neuroprotection would represent a significant advancement in the treatment of hypoxic-ischemic brain injury. Oral TPM has been used to treat neonatal seizures that fail to respond to first-line therapy, but oral administration in newborns is often unreliable, imprecise, and delays attainment of a therapeutic effect (Silverstein & Ferriero, 2008; Filippi et al., 2009).
We have previously completed a low dose, first-in-human study of intravenous TPM in adult patients taking oral TPM for either epilepsy or migraine headaches (Kriel et al., 2010). The patients received a single 25 mg stable-labeled dose of intravenous TPM in addition to their oral TPM regimen. Both the safety and pharmacokinetics results were used to design the phase I investigation reported herein.
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This is the first study investigating the safety and pharmacokinetics of intravenous TPM at clinically relevant doses in subjects not previously exposed to TPM. The results provide new information about TPM. In an earlier, preliminary study in which a subclinical dose (25 mg) of intravenous TPM was given to patients on oral TPM, no serious adverse effects occurred (Kriel et al., 2010). That study provided the basis for the current study in which we investigated the pharmacokinetics and safety of higher doses. Use of healthy volunteers permitted better assessment of the risk and type of adverse effects associated with intravenous TPM that might occur in patients receiving TPM for the first time, as would be the case with neonates.
Intravenous 100-mg TPM doses did not cause any serious adverse effects, but did produce mild central nervous system effects within 15 min following drug administration, indicating rapid diffusion into the central nervous system. This property, which had not previously been characterized, supports the rationale for using intravenous TPM in neonatal seizures, where a rapid onset of action is needed. Furthermore, the intravenous TPM doses, which were given over 15 min, did not cause any changes in vital signs or ECG. Commonly observed adverse reactions known to occur with Topamax, particularly during initiation of therapy include somnolence, dizziness, ataxia, speech disorders and related speech problems, nervousness, psychomotor slowing, abnormal vision, difficulty with memory, paresthesia, diplopia, fatigue, difficulty with concentration or attention, confusion, anorexia, anxiety, and weight decrease (Topamax product label, 2012). As our study was not a full dose ranging trial and only involved a single dose, definitive conclusions about the safety of larger, repeated intravenous TPM doses are not possible. A study involving multiple doses used in clinical practice would permit a more robust investigation of relationship between adverse events and drug concentration.
Absolute bioavailability of oral TPM has been, until now, unknown because no intravenous formulation was available to conduct such as study. In our initial investigation in patients with migraines and epilepsy, we assumed the subjects to be at steady state and found the absolute bioavailability to be 110 ± 16%. [Correction added after online publication 18-March-2013: The absolute bioavailability values have been updated from 97 ± 24%]. The present controlled study in healthy volunteers confirms that observation and permits a more precise determination of TPM bioavailability and bioequivalence. The results from this study further establish that oral TPM is bioequivalent to intravenous TPM with relatively low interpatient variability. Plasma concentrations including peak concentrations attained by intravenous infusion were similar to oral administration, although the Tmax for the oral dose occurred approximately 1.35 h after dose. Should an intravenous TPM formulation be developed for older children and adults needing bridge therapy, the determination that the oral absorption is approximately 100% will simplify the switched from intravenous to oral, or vice versa.
TPM clearances (mean 1.2–1.3 L/kg) after oral and intravenous administration were not statistically different in this study and are similar to previous reports of oral clearance in subjects not taking enzyme-inducing medications (Easterling et al., 1988; Doose et al., 1996; Conway et al., 2003). TPM clearance in healthy volunteers was also similar to the clearance in those not taking inducing co-medication in our previous study of 25 mg doses (1.35 ± 0.37 L/h (Kriel et al., 2010).
As with bioavailability, TPM volume of distribution could not be accurately determined until the development of an intravenous formulation. We found distribution volume to be the same following oral and intravenous administration, and it exhibited relatively low variability (≈25%). Distribution volume is the parameter used to determine loading doses designed quickly to attain targeted drug concentrations. Characterization of TPM's distribution volume, with its low intrasubject variability, permits calculation of intravenous loading doses with good precision. A 1 mg/kg dose would be expected to produce, on average, a Cmax of 1 mg/L with a range of 0.75–1.25 mg/L in two thirds of patients. Future studies investigating the safety of using higher dosing for loading patients are needed.
The mean TPM half-life of 42 h observed in this study was longer than the previously reported value of 21 h (Doose & Streeter, 2002). As confirmation of our result, a similarly long half-life has been reported by Lambrecht et al. (2011). It now appears that TPM has a much longer half-life than previously reported, which may permit less frequent daily dosing than is current practice. In any case, the long half-life suggests that the intravenous TPM may be given once or twice daily while maintaining targeted plasma concentrations.
This study was conducted in healthy volunteers. Future research is needed to determine if intravenous TPM administration can be used for extended periods and at higher doses in adults and children with epilepsy. Intravenous TPM may also be useful in situations where patients on TPM are not able to take medications orally, for example, patients who are undergoing surgery, vomiting, have malabsorption disorders, or who are noncompliant. Safety studies at doses used to load patients are also needed, although patients requiring higher loading doses will likely be in an acute care or hospital setting. Therefore, neurologic and cognitive adverse events, which are more likely to occur with higher doses, may not be as clinically important. Adverse effects would likely be minimal in patients who are switched to intravenous TPM from an oral formulation because drug concentrations after oral and intravenous TPM will be similar when the same dose is given.
The results from this study, combined with substantial evidence of safety in children, set the stage for studies in pediatric populations. Further demonstration of safety and characterization of TPM pharmacokinetics in newborns will inform the design of subsequent controlled clinical trials intended to evaluate the efficacy and safety of intravenous TPM for neonatal seizures.