Development of Parenteral Drugs for the Treatment of Seizure Emergencies
2019-09
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Development of Parenteral Drugs for the Treatment of Seizure Emergencies
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2019-09
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The overall objective of my dissertation is to develop alternative therapies for seizure emergencies. Status epilepticus is a condition defined as a convulsive seizure lasting more than 5 minutes and is considered a seizure emergency due to the increased risk for neuronal damage and mortality (Trinka et al. 2015). Although relatively effective, first-line therapy fails to terminate status epilepticus in 26-57% of cases, leading to increased risk of seizure refractoriness and use of second- and third-line therapies that may increase the risk of systemic complications and mortality (Treiman et al. 1998; Alldredge et al. 2001; Silbergleit et al. 2012; Chamberlain et al. 2014). Three drugs were studied: allopregnanolone (ALLO), lacosamide (LCM) and topiramate (TPM). The pharmacokinetics and pharmacodynamics of investigational allopregnanolone formulations following intravenous and intramuscular delivery were assessed for the development as an early rescue therapy for seizure emergencies (Project 1). I also explored the relationship between lacosamide and PR prolongation in the critically-ill population to identify a subpopulation in whom it can be used safely (Project 2). Finally, for topiramate, the pharmacokinetics and pharmacodynamics of an investigational intravenous formulation was evaluated for adjunctive therapy in seizure emergencies (Project 3). Allopregnanolone, a progesterone derivative and GABAA positive allosteric modulator, has demonstrated potential to treat status epilepticus in preclinical models and pediatric and adult patient case reports. Given that first-line therapy fails in the majority of cases, more effective early treatments are necessary to prevent downstream seizure refractoriness and systemic complications. The specific aims for Project 1 were to characterize the pharmacokinetics, pharmacodynamics and safety following intravenous and intramuscular ALLO in dogs. Five dogs (one on phenobarbital therapy) received single doses of ALLO: one- to four-mg/kg intravenously, or one- to six-mg/kg intramuscularly, with a washout period of at least one week. Plasma samples were collected pre-dose and at regular intervals up to six hours post-dose. Clinical response was assessed by behavioral response and intracranial electroencephalographic (iEEG). I found that with IV ALLO, drug exposure and peak plasma concentration increased proportionally with dose within the doses studied. Behavioral responses and iEEG data illustrate the rapid onset of effect following IV ALLO administration. The results of this study indicate that IV ALLO is a promising agent for the early treatment of seizure emergencies, with evidence of rapid penetration into the brain and a high safety profile. IM ALLO has great potential to be useful as a first-line treatment for SE, but the current formulations do not attain high enough plasma concentrations predicted to confer iEEG changes. Therefore, alternative approached would be needed for a viable IM ALLO product. Intravenous LCM has shown safety and some efficacy as an adjunctive therapy in refractory convulsive and non-convulsive status epilepticus. Outside of seizure emergencies, it is also used in the critically-ill population to treat acute breakthrough seizures or to maintain seizure control in patients who are unable to take oral medications. Lacosamide is particularly appealing in this patient population due to its low potential for drug-drug interactions and serious systemic complications. However, there are reports of PR interval prolongation, which raises concern for patients who have a higher risk for developing cardiac arrhythmias or conduction abnormalities. The specific aim of Project 2 was to estimate the prevalence of PR prolongation in the critically-ill patient population following intravenous LCM administration. I performed a retrospective chart review and defined PR interval prolongation as a shift from normal to high PR interval or an increase of 20% or more in PR interval from baseline. Logistic regression analysis was performed in order to identify clinical factors that help predict PR prolongation or an increase in PR interval >20%. Eight percent of my patient sample experienced PR prolongation, which is 20-times higher than the prevalence of 0.4% reported in ambulatory patients with epilepsy. The logistic regression analysis suggested that the occurrence of PR prolongation following IV LCM administration is positively associated with age, the total daily dose of LCM, and serum potassium levels. However, considering that these results are generated from a small number of events (n=7/88), the true impact of these predictors on PR prolongation in this patient population needs to be explored further. In addition to finding alternative early treatments for seizure emergencies, better adjunctive treatments during refractory stages of status epilepticus are also needed. Topiramate’s many mechanisms of action and preclinical evidence of neuroprotection, which make it an ideal candidate to treat status epilepticus that has become resistant to first-line therapies. Intravenous administration of TPM offers an alternative that would allow more drug to get into the body and at a faster rate than current methods of its administration. The specific aims of Project 3 were to characterize the pharmacokinetics, pharmacodynamics and safety following intravenous TPM in dogs. Five dogs (three on phenobarbital maintenance therapy) were used in this study. Ten and twenty mg/kg of stable-labeled topiramate were infused intravenously over five minutes. One hour following the 10 mg/kg infusion, each dog also received a 5 mg/kg dose of unlabeled oral topiramate. Plasma samples were collected pre-dose and at regular intervals up to nine hours post-dose. Sixteen electrode channels were continuously recorded. Topiramate concentration-time data were analyzed using noncompartmental and population compartmental approaches. Concentration-time data were best fit by a two-compartment model, and co-medication with phenobarbital was associated with a 5.6-fold higher clearance. The estimated absolute oral bioavailability ranged from 62-102%. Statistically significant increases in iEEG activity were observed within 30 minutes of infusion, which is essential when treating seizure emergencies. Simulations suggest a different dosing strategy for dogs on phenobarbital may be necessary to optimize drug exposure. The results of this study indicate that development of an intravenous TPM formulation with evidence of penetration into the brain and good tolerability is feasible. My research suggests that there are promising therapies in development for the management of SE, which will significantly improve patient lives by offering safer use of current antiseizure drugs or more effective therapies. There are many pathways into which these projects can take, including conducting clinical trials in dogs with naturally-occurring SE and single- and multiple-ascending dose studies in patients.
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University of Minnesota Ph.D. dissertation. September 2019. Major: Experimental & Clinical Pharmacology. Advisors: James Cloyd, Lisa Coles. 1 computer file (PDF); xv, 215 pages.
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Vuu, Irene. (2019). Development of Parenteral Drugs for the Treatment of Seizure Emergencies. Retrieved from the University Digital Conservancy, https://hdl.handle.net/11299/209019.
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