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Accepted: 12 February 2018

DOI: 10.1111/epi.14479

SUPPLEMENT ARTICLE

Rescue therapies for seizure emergencies: New modes of

administration

Patricia D. Maglalang1 | Davin Rautiola2 | Ronald A. Siegel2 | Jared M. Fine3 |

Leah R. Hanson3 | Lisa D. Coles1,4 | James C. Cloyd1,4

1
Center for Orphan Drug Research,
University of Minnesota, Minneapolis,
MN, USA
2
Department of Pharmaceutics, College of
Pharmacy, University of Minnesota,
Minneapolis, MN, USA
3
Neuroscience Research at HealthPartners
Institute, St. Paul, MN, USA
4
Department of Experimental and Clinical
Pharmacology, College of Pharmacy,
University of Minnesota, Minneapolis,
MN, USA
Correspondence
James C. Cloyd, Center for Orphan Drug
Research, University of Minnesota,
Minneapolis, MN, USA.
Email: cloyd001@umn.edu
Funding information
University of Minnesota Academic Health
Center Faculty Development Grant;
American Epilepsy Society; Epilepsy
Foundation New Therapies Research
Grant; Ted Rowell Graduate Fellowship;
University of Minnesota Clinical and
Translational Science Institute
Summary
A subgroup of patients with drug‐resistant epilepsy have seizure clusters, which
are a part of the continuum of seizure emergencies that includes prolonged epi-
sodes and status epilepticus. When the patient or caregiver can identify the begin-
ning of a cluster, the condition is amenable to certain treatments, an approach
known as rescue therapy. Intravenous drug administration offers the fastest onset
of action, but this route is usually not an option because most seizure clusters
occur outside of a medical facility. Alternate routes of administration have been
used or are proposed including rectal, buccal, intrapulmonary, subcutaneous, intra-
muscular, and intranasal. The objective of this narrative review is to describe the
(1) anatomical, physiologic, and drug physicochemical properties that need to be
considered when developing therapies for seizure emergencies and (2) products
currently in development. New therapies must consider parameters of Fick's law
such as absorptive surface area, blood flow, membrane thickness, and lipid solu-
bility, because these factors affect both rate and extend of absorption. For exam-
ple, the lung has a 50 000‐fold greater absorptive surface area than that associated
with a subcutaneous injection. Lipid solubility is a physicochemical property that
influences the absorption rate of small molecule drugs. Among drugs currently
used or under development for rescue therapy, allopregnanolone has the greatest
lipid solubility at physiologic pH, followed by propofol, midazolam, diazepam,
lorazepam, alprazolam, and brivaracetam. However, greater lipid solubility corre-
lates with lower water solubility, complicating formulation of rescue therapies.
One approach to overcoming poor aqueous solubility involves the use of a water‐
soluble prodrug coadministered with a converting enzyme, which is being
explored for the intranasal delivery of diazepam. With advances in seizure predic-
tion technology and the development of drug delivery systems that provide rapid
onset of effect, rescue therapies may prevent the occurrence of seizures, thus
greatly improving the management of epilepsy.

KEYWORDS
acute repetitive seizures, benzodiazepines, intramuscular, intranasal, intrapulmonary, rescue therapy,
seizure clusters, subcutaneous

Epilepsia. 2018;59(S2):207–215. wileyonlinelibrary.com/journal/epi Wiley Periodicals, Inc. | 207

© 2018 International League Against Epilepsy

208
| MAGLALANG
1 | INTRODUCTION
A subgroup of patients with drug‐resistant epilepsy have
seizure clusters, also known as acute repetitive seizures.1
This condition is a subset of the continuum of seizure
emergencies that includes prolonged seizures and status
epilepticus (SE). When the patient or caregiver can identify
the onset of a cluster, the condition is amenable to treat-
ment, an approach known as rescue therapy.2 The objective
of such therapy, namely rapid termination of the episode,
is best accomplished by intravenous (IV) administration of
an appropriate drug, typically a benzodiazepine (BZD).3
However, most seizure clusters occur outside of the hospi-
tal, which precludes or delays intravenous administration
unless performed by emergency medical personnel. There-
fore, there is considerable interest in out‐of‐hospital rescue
therapies given by alternate routes of administration.
Characteristics of an ideal rescue therapy for treatment
of seizure clusters include the following: a broad spectrum
of activity, intermediate duration of action, rapid (within
minutes) cessation of seizures, ease of use, safety and mini-
mal discomfort, low inter‐ and intrapatient variability, adult
and pediatric doses/delivery systems, and long shelf life.4
In most situations, oral administration is not a viable treat-
ment option due to slow transit time, choking hazard, or
inability of the patient to swallow. As alternatives to intra-
venous administration, rectal diazepam (DZP) and buccal
midazolam (MDZ)3 are now used as rescue therapies,
whereas other approaches as listed in Table 1 are under
development. In developing a rescue therapy, anatomic and
physiologic factors associated with a route of administra-
tion must be considered along with physicochemical prop-
erties of the drug.
2 | ANATOMIC AND PHYSIOLOGIC
FACTORS AFFECTING DRUG
ABSORPTION
When considering rescue therapy administered by routes
other than intravenous administration, the rate and extent
of drug absorption from a tissue is a paramount concern.
These processes are largely governed by Fick's law:
Diffusion Coefficient * Partition Coefficient * Surface Area * Concentration Gradient
Diffusion Rate ¼
Membrane Thickness
Anatomic/physiologic factors of the tissues involved in
alternate routes of administration include the absorptive sur-
face area, diffusion coefficient, blood flow, and membrane
thickness. As shown in Table 2, there are substantial
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ET AL.
Key Points
• Rectal, buccal, intramuscular, intranasal, subcuta-
neous, and intrapulmonary routes are currently
used or are under development as rescue thera-
pies
• New therapies must take into consideration
parameters of Fick's law such as absorptive sur-
face area, blood flow, and lipid solubility
• Lipid solubility is the most important drug
physicochemical property influencing the absorp-
tion rate of small molecule drugs
• Greater lipid solubility correlates with lower
water solubility, complicating the formulation of
rescue therapies
• One approach to overcoming poor aqueous solu-
bility involves the use of a water-soluble prodrug
coadministered with a converting enzyme
differences in the surface areas and perfusion of tissues
exposed to drug at the administration site. Blood flowing
through the capillary beds in these tissues acts as a sink, car-
rying drug away from the site by advection and maintaining
a concentration gradient. More highly perfused tissues tend
to have higher capillary densities, thereby reducing the dis-
tance in the tissue through which the drug must diffuse
before reaching the blood. For example, differences in the
vascularity of skeletal muscle in the arm, thigh, and buttocks
can account for the different drug absorption rates observed
following intramuscular (IM) injections of the same drug
(rate: arm > thigh > buttocks).5
In most cases for a given drug, the greater the absorp-
tive surface area and blood flow, the faster drug absorption
takes place. As a general rule, the rate of absorption differs
by route with intrapulmonary (IP) being greater than intra-
nasal (IN) followed by rectal, buccal, IM, and subcuta-
neous (SC). The lungs have the greatest absorptive surface
area and a very high perfusion rate. Furthermore, the alveo-
lar‐capillary membrane is exceptionally thin (2‐0.6 μm).
These factors render IP delivery as an attractive route for
drugs that must be absorbed quickly. The nasal epithelium
is also quite thin, 40‐80 μm,18 compared to rectal and buc-
cal epithelia, 160‐190 μm and 500‐800 μm, respec-
tively.19,20 The porous epithelium in the olfactory region of
the nasal cavity and olfactory nerve bundle offers the
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MAGLALANG ET AL. | 209

T A B L E 1 Summary of rescue therapies under development

Drug Route Sponsor Status Orphan designationa
Diazepam Rectal Valeant (US) Marketed Yes
Actavis (EU)
Generics
Intranasal Neurelis Final studies underway. FDA has Yes
conferred fast‐track designation.
Projected 505(b)2 submission
in 8‐15 months
Diazepam prodrug Intranasal University of Minnesota Preclinical; investigational new drug No
enabling studies underway
Intramuscular Pfizer Development discontinued Yes
Subcutaneous Xeris Preclinical Yes
Propofol prodrug(s) TBD Epalex Preclinical studies underway Yes
Midazolam Intranasal Proximagen Clinical studies completed. FDA Yes
has conferred fast‐track designation.
Projected 505(b)2 submission
in 3‐6 months
Intramuscular Pfizer DoD & BARDA pursuing FDA Yes (SE)
approval for SE. Following approval,
Pfizer plans to make autoinjector
available to health care professionals.
Buccal Shire Marketed in selected European countries Yes (Shire)
Buccolumb Specialty Products
Epistatus
Alprazolam Intrapulmonary Engage Therapeutics Phase II No
Brivaracetam TBD UCB Preclinical studies No
Allopregnanolone TDB UC‐Davis Preclinical studies No
a
Refers to a drug product intended to treat a rare disease or condition that has been granted orphan status by the FDA in accordance with requirements of the Orphan
Drug Act and Agency regulations. https://www.fda.gov/ForIndustry/DevelopingProductsforRareDiseasesConditions/HowtoapplyforOrphanProductDesignation/default.
htm
b
Midazolam oromucosal solution marketed by Shire.

potential for direct nose to brain drug delivery.21 Drugs
delivered by the IM or SC routes do not need to cross an
epithelial layer, but the drug depot at the injection site has
a limited surface area, resulting in relatively low tissue per-
fusion and, thus, slow absorption. The volume of drug
solution that can be instilled or injected into the tissue or
cavity should also be considered. Relatively large volumes
(mLs) can be administered buccally or rectally, whereas the
IN route is limited to a few hundred microliters.22
3 | DRUG PHYSICOCHEMICAL
CHARACTERISTICS THAT AFFECT
DRUG ABSORPTION
The partition coefficient in Fick's law reflects a drug's lipid
solubility. Lipid‐soluble drugs tend to partition from polar
aqueous environments into the nonpolar environment of
lipid membranes. Partitioning has a major influence on sys-
temic pharmacokinetics (PK) and the drug's ability to cross
the blood–brain barrier (BBB). Partition coefficient (LogP)
and polar surface area are common metrics used to describe
lipid solubility.23 As shown in Table 3, most of the drugs
used or under development for rescue therapy have high
LogP values and small polar surface areas, indicating high
lipid solubilities.
Lipophilic drugs usually have poor water solubility.
However, drugs must be in solution to diffuse across bio-
logic membranes. Formulation of lipophilic drugs typically
necessitates the use of organic cosolvents such as alcohol
or glycols, which can increase drug concentration in a
formulation while limiting the volume required to deliver
a clinically relevant dose. Organic cosolvents can also
have toxic effects, particularly in sensitive tissues exposed
to high cosolvent levels.25,26 One drug formulation used
for seizure emergencies that avoids the use of cosolvents
is MDZ injectable, USP, which has a pH of approxi-
mately 3 creating an open‐ring, water‐soluble configura-
tion. Upon exposure to physiologic pH, the ring closes,
resulting in a highly lipophilic form.27 However, the
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210
| MAGLALANG ET AL.

T A B L E 2 Important physiologic factors for common routes of with a relatively small absorptive surface is employed
administration for rescue therapy, drugs with poor lipid solubility will
Route Surface area (m2) Perfusion (mL/min/100 g) have slower rates of diffusion and, thus, a slower onset
Oral 260‐400 6,7
40‐1608
of effect. A comparison of Tmax following IM adminis-
9 tration of LZP, DZP, and MDZ illustrates this concept.
Pulmonary 70‐140 540‐294008
In a PK study in healthy volunteers in which LZP was
Rectal 0.015‐0.0410 9.0‐2411,12
given IM, Tmax was 3 hours following IM injection.29
Intranasal 0.015‐0.02513 30‐3614 Garnett et al30 carried out a study in healthy subjects
15,16
Buccal 0.003‐0.005 20.317 evaluating IM DZP and found a mean Tmax of 52 min-
Intramuscular ~0.002 3.0‐608 utes. In contrast, Reichard et al,31 using a similar study
Subcutaneous ~0.002 0.90‐5.68 design, reported that the Tmax for IM MDZ was 30 min-
utes. These studies highlight the importance of lipid sol-
ubility when selecting a candidate drug for development
as rescue therapy.
T A B L E 3 Physicochemical properties of putative rescue
therapies24

Molecular Polar surface 4 | ALTERNATIVES TO IV

Drug weight (g/mol) cLogP area (A2) ADMINISTRATION OF RESCUE
Midazolam 325.8 4.3 30.2 THERAPIES
Diazepam 284.7 2.8 32.7
Lorazepam 321.2 2.4 61.7
Following the introduction of rectal DZP and buccal MDZ,
there has been increasing effort to develop rescue therapies
Alprazolam 308.8 2.1 43.1
employing other routes of administration.
Allopregnanolone 318.3 4.9 37.3
Brivaracetam 212.3 1.0 63.4
Propofol 178.3 3.8 20.2
4.1 | Intrapulmonary
cLogP, calculated partition coefficient. IP administration offers the potential for rapid onset of
drug action, which makes this route desirable for rescue
acidic pH of the MDZ parenteral formulation can also therapy. The therapeutic efficacy of inhaled drugs depends
cause tissue injury. on the extent and site of deposition in the respiratory tract.
The effect of lipid solubility on PK and, subsequently, The large surface area of alveoli in the lungs allows for
pharmacodynamics (PD) was studied by Arendt et al,28 efficient absorption of small molecules into the capillaries
who compared 3 BZDs used in treating seizure emergen- and then into the systemic circulation.32 Often it is difficult
cies to illustrate the complex effects of lipid solubility on to determine the amount of material deposited in specific
PD. Cats with implanted electroencephalography (EEG) regions of the respiratory tract, making dose determination
electrodes were administrated IV DZP, lorazepam (LZP), issues more complex. The size, shape, and flow characteris-
or MDZ. The onset of slow wave activity, a marker of tics of aerosolized drug particles must be tightly controlled
BZD activity, was correlated with lipid solubility. MDZ to ensure adequate deposition in the alveolar region.33
had the earliest onset of effect, 0.29 minutes; followed by Poorly soluble drug particles at high exposure concentra-
DZP, 0.89 minutes; then LZP, 3.8 minutes. However, LZP, tions can impair lung clearance and have been shown to
the least lipid soluble among the 3 drugs, had a longer resi- result in tumor formation in rats as a nonspecific
dence time in the brain resulting in a longer duration of response.34 Because of the sensitive nature of lung tissue, a
effect, 28.3 minutes. In comparison, the duration of effect US Food and Drug Administration (FDA) guidance for
for DZP and MDZ was 6‐7 minutes because these drugs industry recommends thorough characterization of the drug
more rapidly redistributed to muscle and adipose tissue. and excipients, with additional comprehensive controls for
Given the very large absorptive area of the BBB, the dif- strength, quality, and purity.35
ference in onset of effect of LZP as compared to DZP and In addition to the physicochemical properties of the
MDZ was minor, while its duration of effect was 4‐fold drug formulation and mechanism of the delivery device,
greater than the other 2 drugs. ergonomic and physiologic constraints for specific patient
Differences in lipid solubility may not be critically populations should be considered. IP drug products
important when BZDs are administered intravenously; designed for adult patients may not be suitable for pediatric
however, lipid solubility plays a crucial role if adminis- or geriatric patients. Furthermore, the pathophysiologic
tering these drugs by an alternate route. When a route changes in patients experiencing a seizure (eg, tachypnea,

MAGLALANG ET AL.
hypopnea, apnea, stridor, postictal cough, and neurogenic
pulmonary edema)36 could limit drug deposition.
Inhalation studies have numerous experimental vari-
ables, and thus studies must be highly standardized to
enable reproducible results and meet regulatory require-
ments compared to other routes of administration.37
Engage Therapeutics is developing IP alprazolam admin-
istered via their Staccato System.38 The system utilizes a
heat package with a stainless steel plate, onto which a thin
film of drug is coated. A single normal inhalation activates
the system, causing the plate to instantaneously heat and
sublimate the drug, which then condenses into small parti-
cles that are delivered to the vascularized tissue of the deep
lung. As shown in Figure 1, following IP administration,
alprazolam's Tmax is approximately 2 minutes.39 However,
only drugs that are thermally stable and have a high vapor
pressure are suitable for thermal vaporization aerosol
devices, which limits the number of compounds that can be
administered by this approach.40 Because alprazolam does
not have an indication for seizures, one or more phase III
clinical trials will likely be needed for FDA approval.
4.2 | Subcutaneous
Subcutaneous drug administration offers the benefits of
easy access and administration. However, the volume of an
SC dose should be less than 2 mL to avoid adverse events
at the injection site, such as injection pain and leakage.41
This volume limitation precludes the formulation with ther-
apeutically relevant concentrations of many lipophilic drugs
without the use of organic solvents or other solubilizing
agents, which may irritate tissues and lead to induration,
sloughing, or abscess formation.26,42 If frequent injections
are necessary, the injection site should be rotated to allow
time for the tissue to recover. Correctly performing a man-
ual SC injection requires training and some psychomotor
skill, so automated devices are preferred to ensure consis-
tent delivery.
F I G U R E 1 Intrapulmonary delivery of alprazolam in healthy
volunteers over 3 doses. Squares indicate 2.0 mg dose (n = 8),
diamond 1.0 mg (n = 20) dose, and triangle 1.0 mg (n = 8) dose
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| 211
Xeris Pharmaceuticals, Inc. is developing an autoinjec-
tor SC DZP formulation. This system offers advantages
including ease of use and an estimated 2‐year shelf life.
The company proposes that the product will have an injec-
tion volume ≤200 μL to deliver a therapeutic dose. In a
rodent study, the PK profile, including Tmax of approxi-
mately 30 minutes, was statistically equivalent to IM
DZP.43 This product is currently in preclinical develop-
ment, has orphan designation, and investigational new drug
enabling studies are underway.
4.3 | Intramuscular
IM delivery shares many of the same advantages and draw-
backs as SC. Among the limitations is a relatively slow
rate of drug absorption compared to IP or IN routes and
the risk of improper injection. A longer needle is needed is
needed (1‐1.5 inches) to pass through the SC adipose tissue
and reach the muscle. The thickness of the adipose tissue
depends on the injection site location and varies signifi-
cantly within patient populations. For example, obese or
emaciated patients would require different needle sizes.
However, there is a lower instance of injection site reac-
tions with IM delivery compared to SC.44
More than 30 years ago Jawad et al45 reported that IM
MDZ compared favorably with IV DZP in terms of onset
of reduction in spike wave activity in a group of patients
with epilepsy. This set the stage for the subsequent devel-
opment of IM MDZ for seizure emergencies using autoin-
jector technology. A phase I study in 39 healthy volunteers
showed rapid absorption over a range of 5‐30 mg doses
administered using an IM autoinjector.31 Following a
15 mg dose, the mean Cmax and Tmax were 197 ng/mL and
0.5 h, respectively. A subsequent phase III trial demon-
strated that IM MDZ using an autoinjector was superior to
a clinically relevant IV LZP dose for treatment of SE when
both are administered by paramedics.46 The primary out-
come, absence of seizures upon arrival in the emergency
department, was achieved in 73% of patients in the IM
MDZ group vs 63% given IV LZP. Pfizer states that the
US Departments of Defense and Health and Human Ser-
vices are pursuing FDA approval for the IM autoinjector
MDZ product. Should approval be granted, Pfizer plans to
market this autoinjector to health care professionals.47
4.4 | Intranasal
Nasal administration is inherently attractive as it has the
potential for faster drug administration and absorption,
requires minimal training, is easily performed, and carries
little risk of injury. Onset of effect, at least with MDZ,
may be faster than other non‐IV routes of administration.
Rapid distribution into the central nervous system (CNS) is
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212
| MAGLALANG ET AL.

supported by EEG studies, for example, Hardmeier et al48

and Scott et al.49 Rapid distribution may also contribute to
a higher frequency of CNS side effects as compared to rec-
tal DZP, but these appear to be in line with those observed
following comparable doses of IV DZP.50
Drugs deposited in the nasal cavity are transported later-
ally toward the nasopharynx at a rate of 5‐6 mm/min by
beating cilia on the surface of the mucosa. With a transit
time of 15‐20 minutes, this mucociliary clearance could
remove drug from the nasal cavity before the full dose is F I G U R E 2 Mean midazolam plasma concentrations over time
absorbed into the nasal mucosa and lead to subtherapeutic (A) for healthy volunteers vs patients with epilepsy, and mean change
plasma concentrations.51 Lower bioavailability can also from baseline (B) in Stanford Sleepiness Scale (SSS) over time.
result from larger dose volumes. The nasal cavity accommo- Green circles indicate patients with epilepsy and blue circles indicate
dates up to 200 μL of solution. Excess volume tends to healthy participants. (Reproduced from Bancke LL, Dworak HA,
Rodvold KA, et al. Pharmacokinetics, pharmacodynamics, and safety
drain into the nasopharynx or out of the anterior nares.52
of USL261, a midazolam formulation optimized for intranasal
Solubilizers used to formulate BZDs at concentrations high
delivery, in a randomized study with healthy volunteers. Epilepsia.
enough to avoid drainage can irritate the mucosa and result
2015;56: 1723–31 with permission from the publisher, Wiley)
in significant discomfort.22 A patient's pathophysiologic
state, such as sinusitis or ictal nasal secretions, could lead to
variations in absorption rates and bioavailability for IN‐
delivered drugs. Therefore, nasally administered BZDs for
treatment of seizure emergencies must possess certain char-
acteristics: (1) high and consistent absorption, (2) rapid onset
of effect, and (3) minimal irritation of sensitive nasal tissues.
Proximagen, Ltd. (formerly Upsher Smith Laboratories)
is developing IN MDZ. In a phase I study,53 the Tmax aver-
aged 10‐12 minutes at doses from 2.5‐7.5 mg (Figure 2A),
whereas the absolute bioavailability ranged from 62‐73%.
At doses up to 7.5 mg, the onset of CNS side effects such
as psychomotor impairment and sedation occurred within
15 minutes, but these measures returned to baseline values
by 4 hours (Figure 2B). Other adverse effects included
nasal discomfort (84%), throat irritation (84%), and F I G U R E 3 Mean plasma concentration time profiles of diazepam
increased lacrimation (76%). The company reports that it after intravenous and intranasal administration in healthy volunteers.
has completed its clinical studies and that a new drug Squares indicate NRL‐1 solution, 10.0 mg dose and triangle indicate
application is in preparation.54 intravenous solution, 5.0 mg dose. (Reproduced with permission from
Neurelis, Inc has developed a vitamin E–based formula- Elsevier B.V. in Agarwal et al.55)
tion, which increases DZP solubility to 10 mg/100 μL.55
Figure 3 shows the concentration‐time profile of IN DZP
solution (10 mg) vs IV DZP (5 mg).56 The IN formulation
had a Cmax of 272 ng/mL, Tmax of 1.5 h, and 97% absolute
bioavailability. In a subsequent PK study involving healthy
volunteers, the Tmax and Cmax values were comparable to
the same dose given rectally, but with markedly reduced
variability (Figure 4).55
A group from University Hospital Basel led by Haschke
developed a highly concentrated cyclodextrin‐based IN
MDZ. When coupled with chitosan, an absorption enhan-
cer, the formulation attained a Tmax and Cmax of 7.2 min-
utes and 81 ng/mL, respectively.57 A subsequent study F I G U R E 4 Weight/dose adjusted comparison of rectal and
evaluated the PK and PD of this formulation vs IV admin- intranasal (NRL‐1) diazepam of area under the curve (AUC) in
istration in healthy volunteers. After IN doses of 3 and 6 healthy volunteers. In this crossover study, 28 subjects were used in
mg, Cmax (52 and 98 ng/mL) and AUC values (96 and the 20 mg group and 17 subjects in the 15 mg group

MAGLALANG ET AL.
F I G U R E 5 Mean (± standard deviation) concentration time
profile (A) of DZP in plasma following 1.6 mg/kg dose of IN AVF
dose at AVF (1.1 mg/kg dose of DZP) plus enzyme (AOP) in rats.
Blood was collected at 5, 15, 30, 60, and 90 min. Blue circles
indicate each time point (n = 3 per time point). Comparison of DZP
in brain and plasma concentrations (B) after 5 min postdose in 3 rats
185 ng*h/mL) were dose proportional, and both doses dis-
played similar Tmax values (7.6 and 8.4 minutes).48 The
status of development for this formulation is unknown.
Our group at the University of Minnesota is developing a
novel IN drug delivery system involving a water‐soluble
BZD prodrug combined with a converting enzyme, which
are admixed at the time of administration. As a first iteration,
avizafone (AVF), a water‐soluble DZP prodrug, was com-
bined with Aspergillus oryzae protease (AOP).58 AOP con-
verts AVF to DZP within minutes, resulting in a
supersaturated concentration of the active drug in the nasal
mucosa. A pilot PK study evaluated this system in rats. As
shown in Figure 5A, following IN administration of 1.6 mg/
kg, a Cmax of 450 ng/mL was attained at the first blood sam-
ple collection (5 minutes post‐dose). The brain and plasma
DZP concentrations (Figure 5B) at 5 minutes postdose were
similar with a mean brain‐to‐plasma ratio of 0.88 ± (stan-
dard deviation) 0.08, suggesting very quick equilibration
between blood and the central nervous system. Concentra-
tion time profiles reported in this study are comparable to
those reported elsewhere using IV administration of DZP
doses similar to those we used in our study,59 indicating that
the majority of the prodrug is transformed to the active drug
and absorbed through the nasal mucosa. This pilot study
demonstrated the feasibility of using a prodrug and convert-
ing enzyme as a novel drug delivery system for rescue ther-
apy. The supersaturated DZP concentrations at the site of
administration should result in very rapid absorption, offer-
ing the potential for earlier onset of action. Since these initial
studies we have determined that human aminopeptidase B,
which is already present at low levels in nasal tissues, also
rapidly converts AVF to DZP.
4.5 | Other drug candidates for rescue
therapies
Although BZDs are the drugs of choice for treating seizure
emergencies, there is interest in evaluating other drugs such
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| 213
as allopregnanolone and brivaracetam as rescue therapies.
The groups developing these products are investigating IM
administration as the method of drug delivery (see Table 1).
5 | CONCLUSION
The number of approaches and products to treat seizure
clusters and other seizure emergencies is expanding. Each
approach has advantages and disadvantages in terms of
ease of use, onset and duration of action, and adverse
effects. Anatomic and physiologic factors and physico-
chemical properties are the main determinates controlling
drug selection and route of administration. Table 1 summa-
rizes the status of rescue therapies currently under develop-
ment. These new approaches offer ease of use and
convenience, and may lead to faster time of seizure cessa-
tion, resulting in fewer emergency department visits and
improved quality of life. Advances in seizure prediction
technology combined with the development of drug deliv-
ery systems that provide rapid onset of effect have the
potential to prevent seizures from occurring. Such
approaches could reduce or eliminate the need for chronic
oral drug therapy, thereby radically altering the treatment
paradigm for epilepsy.
ACKNOWLEDGMENTS
The prodrug study presented in this narrative review was
funded by University of Minnesota Academic Health Cen-
ter Faculty Development Grant, American Epilepsy Soci-
ety, Epilepsy Foundation New Therapies Research Grant,
Ted Rowell Graduate Fellowship, and University of Min-
nesota Clinical and Translational Science Institute. We
would like to acknowledge Drs. Gunda Georg and Narsih-
mulu Cheryala who synthesized avizafone and Ms. Usha
Mishra for assisting with the diazepam assay.
DISCLOSURE OF CONFLICT OF INTEREST
Drs. Cloyd and Siegel have 2 patents pending for the nasal
delivery methods and prodrug/converting enzyme system.
Dr. Cloyd is a co‐principal investigator and a consultant to
Xeris Pharmaceuticals and a consultant to Neurelis, Inc.
and UCB. The remaining authors have no conflicts of
interest. We confirm that we have read the Journal’s posi-
tion on issues involved in ethical publication and affirm
that this report is consistent with those guidelines.
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How to cite this article: Maglalang PD, Rautiola D,
Siegel RA, et al. Rescue therapies for seizure
emergencies: New modes of administration.
Epilepsia. 2018;59(S2):207–215. https://doi.org/
10.1111/epi.14479