Topiramate (TPM) is used in adults and children, age 2 and older, for the treatment of epilepsy and, in adults, for the prevention of migraine headaches. It possesses a broad range of pharmacologic actions: blockade of voltage-gated sodium channels, augmentation of certain subtypes of γ-aminobutyric acid (GABA)A receptors, inhibition of α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) and kainate glutamate ionotropic receptors, and weak inhibition of some isoenzymes of carbonic anhydrase (CA-II and CA-IV). There is a growing body of evidence that TPM is 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).
Neonatal seizures are a relatively rare, but serious medical problem. The most common cause is hypoxic-ischemic brain injury, which has a high mortality rate and grave neurologic sequelae (Ronen et al., 1999). The occurrence of seizures in conjunction with hypoxic-ischemic injury is thought to exacerbate subsequent neurologic problems (Holden et al., 1982; Sheth et al., 1999; Tekgul et al., 2006). In an open label trial, the current drugs of choice, phenobarbital and phenytoin, for treating neonatal seizures were effective in less than 50% of newborns (Painter et al., 1999). In addition to their uncertain efficacy, both drugs are associated with serious adverse effects (Painter et al., 1999; Bittigau et al., 2003; Glier et al., 2004).
Based on promising results from laboratory studies, orally administered TPM has been used to treat neonatal seizure when first-line therapy fails (Silverstein & Ferriero, 2008; Glass et al., 2011). Silverstein & Ferriero (2008) reported the results of a survey of 55 child neurologists regarding their choice of a second-line, add-on antiepileptic drug in the treatment of neonatal seizures. The leading add-on candidates were topiramate (recommended by 55%) and levetiracetam (recommended by 47%). Among those recommending topiramate, 70% perceived treatment to be beneficial and 63% perceived no side effects. In addition to use as an antiepileptic drug, oral topiramate has recently been studied for use in hypothermic newborns with hypoxic-ischemic encephalopathy, but thus far studies have focused on safety and pharmacokinetics (Filippi et al., 2009, 2010). When TPM is used to treat neonatal seizures an extemporaneously compounded oral solution of unknown stability is typically administered through a gastrointestinal tube.
An injectable TPM formulation could improve the treatment of neonatal seizures by ensuring more precise, reliable dosing (Glass et al., 2011). Furthermore, injectable TPM would be useful as bridge therapy in older children and adults on oral topiramate when they are unable to take medications by mouth. Although TPM solubility in water (maximum = 9.8 mg/ml) would permit manufacturing of an intravenous solution suitable for adults and older children, a more concentrated formulation is desirable for newborns so as to limit the fluid volume administered with a dose (Janssen Pharmaceuticals, Inc, 2012).
New drugs and formulations typically must first be evaluated in adults and older children before beginning studies in neonates, Therefore, this report presents the results of a first-in-human study of intravenous topiramate (IV TPM). The aims were to determine the safety and pharmacokinetics of IV TPM in adult patients on maintenance TPM therapy. To accomplish the latter aim, we used a stable-labeled TPM formulation, which permitted rigorous characterization of oral and IV TPM pharmacokinetics, including absolute bioavailability, distribution volume, clearance, and elimination half-life under steady-state conditions without interrupting maintenance therapy (Baillie, 1981).
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An intravenous TPM formulation would be useful in the treatment of neonatal seizures as well as in providing bridge therapy for older children and adults in whom oral TPM is interrupted. Before studies in neonates can be done, the pharmacokinetics and safety of TPM typically must be evaluated in adults. This pilot phase I study is a first-in-human investigation of intravenous TPM safety and pharmacokinetics.
Topiramate therapy is associated with significant verbal function, memory, and attention impairment in healthy volunteers and patients with epilepsy (Meador et al., 2003; Blum et al., 2006). We choose to first study intravenous TPM in patients on long-term oral TPM therapy in order to minimize the potential for adverse effects. Furthermore, we used a small dose so as to limit the effects of increased plasma TPM concentrations. Although we observed only minor adverse events; a larger dose or administration to subjects naive to TPM would more likely result in clinically important adverse events.
The use of an injectable, stable-label formulation given simultaneously to patients on maintenance TPM therapy along with a liquid chromatography-mass spectroscopy assay allowed us to measure both labeled (IV) and unlabeled (oral) TPM and, thus characterize aspects of TPM pharmacokinetics not previously known.
The use of an IV formulation along with the oral product, permitted the first ever determination of TPM absolute bioavailability, which is approximately 100% with modest interpatient variability. This suggests that clinicians can be reasonably confident that poor or wide variability in absorption is not a likely cause of poor response. Knowing that TPM is completely absorbed also permits use of the same dose intravenously when oral therapy is interrupted.
For the same reasons that apply to absolute bioavailability, this is the first study reporting the absolute volume of distribution. The distribution volume, 0.8 L/kg, we determined agrees with previous reports, of 0.6–0.8 L/kg. (Garnett, 2000) and exhibits relatively low variability. Information about distribution volume permits calculation of intravenous loading doses to quickly and accurately attain targeted TPM concentrations. However, studies are needed to investigate the safety of using higher loading doses in patients.
Our study is also the first to characterize TPM absolute clearance and elimination half-life under steady-state conditions. TPM elimination involves both metabolism and excretion of the parent drug in the urine. Approximately 20% of TPM is metabolized when administered in the absence of enzyme inducers (Wu et al., 1994). When TPM is administered with an enzyme inducer, the apparent metabolic clearance doubles (Gisclon et al., 1994; Sachdeo et al., 1996; Garnett, 2000). Our study, using an intravenous formulation which avoids intestinal metabolism, confirms that the effect of enzyme inducers is primarily in the liver and not in intestinal tissue. We found a fivefold range in clearances, from 0.84 to 4.23 L/h, which likely contributes to the substantial variability in dosing requirements.
The use of a stable-labeled intravenous formulation also allowed us to characterize TPM elimination half-life under steady-state conditions. Previous studies in either healthy volunteers or patients given a single or multiple TPM doses reported an average half-life of 21 h (Easterling et al., 1988; Doose et al., 1996; Johannessen, 1997). Information about the steady-state half-life of TPM in the presence of enzyme-inducing drugs had not been reported. We found half-life in induced patients was similar to that in earlier reports, but TPM half-life in uninduced patients was substantially longer, 31 h, than values obtained following single doses. Our results indicate, that regardless of concomitant therapy many patients may be able to take immediate release oral TPM on a once daily basis.
Impaired renal function and advanced age decrease TPM clearance (Doose & Streeter, 2002). However, we found no effect of age or renal function on TPM pharmacokinetics, which was expected given that our patients had were relatively young and had creatinine clearances in the normal range.
We used a small intravenous dose for this first-in-human study to obtain preliminary safety and pharmacokinetic data prior to initiating the next phase of the project, a safety and bioequivalence study comparing a clinically relevant intravenous TPM dose with the commercially available oral tablet, which has now been completed (Clark et al., 2013). Results from these pilot phase I studies in adults support further evaluation of intravenous TPM in adults, children, and newborns.