Acta Neurol Scand 2008: 118: 69–86 DOI: 10.1111/j.1600-0404.2008.01004.x
`
`Copyright Ó 2008 The Authors
`Journal compilation Ó 2008 Blackwell Munksgaard
`ACTA NEUROLOGICA
`SCANDINAVICA
`
`Review Article
`Benzodiazepines in epilepsy: pharmacology
`and pharmacokinetics
`
`Riss J, Cloyd J, Gates J, Collins S. Benzodiazepines in epilepsy:
`pharmacology and pharmacokinetics.
`Acta Neurol Scand 2008: 118: 69–86.
`Ó 2008 The Authors Journal compilation Ó 2008 Blackwell Munksgaard.
`
`Benzodiazepines (BZDs) remain important agents in the management
`of epilepsy. They are drugs of first choice for status epilepticus and
`seizures associated with post-anoxic insult and are also frequently used
`in the treatment of febrile, acute repetitive and alcohol withdrawal
`seizures. Clinical advantages of these drugs include rapid onset of
`action, high efficacy rates and minimal toxicity. Benzodiazepines are
`used in a variety of clinical situations because they have a broad
`spectrum of clinical activity and can be administered via several routes.
`Potential shortcomings of BZDs include tolerance, withdrawal
`symptoms, adverse events, such as cognitive impairment and sedation,
`and drug interactions. Benzodiazepines differ in their pharmacologic
`effects and pharmacokinetic profiles, which dictate how the drugs are
`used. Among the approximately 35 BZDs available, a select few are
`used for the management of seizures and epilepsy: clobazam,
`clonazepam, clorazepate, diazepam, lorazepam and midazolam.
`Among these BZDs, clorazepate has a unique profile that includes a
`long half-life of its active metabolite and slow onset of tolerance.
`Additionally, the pharmacokinetic characteristics of clorazepate
`(particularly the sustained-release formulation) could theoretically
`help minimize adverse events. However, larger, controlled studies of
`clorazepate are needed to further examine its role in the treatment of
`patients with epilepsy.
`
`J. Riss1, J. Cloyd1, J. Gates2,
`S. Collins3
`1Center for Orphan Drug Research, Department of
`Experimental and Clinical Pharmacology, College of
`Pharmacy, University of Minnesota, Minneapolis, MN,
`USA; 2Minnesota Epilepsy Groupâ, St Paul, MN, USA;
`3Ovation Pharmaceuticals, Inc., Deerfield, IL, USA
`
`Key words: benzodiazepines; epilepsy;
`pharmacokinetics; pharmacology; clorazepate
`
`James Cloyd, PharmD, McGuire Translational Research
`Facility, 2001 6th Street SE, Minneapolis, MN 55455,
`USA
`Tel.: +1 612 624 4609
`Fax: +1 612 626 9985
`e-mail: cloyd001@umn.edu
`
`Accepted for publication January 28, 2008
`
`Introduction
`
`Much attention has been focused on the introduc-
`tion of new antiepileptic drugs (AEDs) into the US
`market during the past 15 years. Nonetheless,
`benzodiazepines (BZDs), which have been used
`since the 1960s, remain important
`in epilepsy
`management and are the drugs of first choice for
`status epilepticus and seizures associated with post-
`anoxic insult. Benzodiazepines also continue to
`play major roles in treating other conditions such
`as febrile seizures, acute repetitive seizures and
`alcohol withdrawal seizures. The major clinical
`advantages of BZDs are high efficacy rates, rapid
`onset of action and minimal toxicity. Few other
`drugs possess comparable attributes.
`
`All BZDs share similar neuropharmacologic
`properties including anxiety reduction, sedation,
`sleep induction, anticonvulsant effects and muscle
`relaxation (1). There are, however, differences
`among BZDs in affinity for receptor subtypes,
`which may produce different pharmacologic
`effects. Thus, some BZDs are more effective than
`others as anticonvulsants; few of the approxi-
`mately 35 BZDs available worldwide (2) are used
`for managing epilepsy. Diazepam and lorazepam
`are primarily used for management of seizure
`emergencies, whereas clobazam, clonazepam and
`clorazepate are commonly used in chronic epilepsy
`management. Midazolam often is used as an
`alternative to diazepam and lorazepam in seizure
`emergencies and for treating refractory status
`
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`Riss et al.
`
`epilepticus. The BZDs also have widely varying
`pharmacokinetic profiles, with differences
`in
`absorption, onset and duration of action and
`formation of active metabolites. Thus, pharmaco-
`kinetic differences often dictate the use of specific
`BZDs, route(s) of administration and formula-
`tion(s). Additionally, the nature and importance of
`side effects and drug interactions have been iden-
`tified and clarified in recent years.
`The purpose of
`this review was to provide
`clinicians with information for selecting BZDs
`and for managing BZD therapy in their patients.
`The article considers BZD pharmacology, phar-
`macokinetics, use in epilepsy management, toler-
`ance and withdrawal. Also included in this review
`is an analysis and discussion of the effects of missed
`daily doses of immediate- and extended-release
`plasma N-des-
`clorazepate
`formulations
`on
`methyldiazepam (DMD) concentrations.
`
`Benzodiazepine pharmacology
`
`There are three principal c-aminobutyric acid
`(GABA) receptor subtypes. Ligand-activated ion
`channels that are selectively blocked by bicuculline
`and modulated by steroids, BZDs, and barbitu-
`rates are known as GABAA receptors (3). The
`second receptor subtype, GABAB, consists of
`G-protein-coupled,
`seven-transmembrane recep-
`tors, which are selectively activated by (R)-())-
`baclofen and 3-aminopropylphosphinic acid and
`are blocked by phaclofen (3). Transmitter-gated
`chloride channels, GABAC receptors, are selec-
`tively
`activated by
`certain conformationally
`restricted GABA analogs and are not modulated
`by steroids, BZDs or barbiturates (3).
`Benzodiazepines bind to GABAA receptors,
`ionotropic transmembrane proteins located in the
`neuronal membranes of
`the
`central nervous
`system (CNS) (3). The GABAA receptor consists
`of a pentameric structure with multiple subunits
`that are necessary for normal physiologic func-
`tion. The receptor subunits are assembled from
`combinations of 19 polypeptides (i.e. a1–6, b1–3,
`c1–3, d, e, p, h and q1–3) (4); different subunit
`combinations determine the pharmacologic prop-
`erties of the receptor (5, 6). The number and
`types of subunits vary depending on the location
`of the receptor in the CNS (7). The inhibitory
`neurotransmitter GABA binds to the receptor to
`open the chloride ion gates and produce an
`inhibitory current (6, 8). Binding of BZDs to the
`c subunit of the receptor is important in the
`potentiation of GABAergic inhibition (9). Differ-
`entiation between BZDs and GABA is impor-
`tant. Benzodiazepines do not
`substitute
`for
`
`70
`
`GABA, but instead enhance the inhibitory effects
`of GABA. Benzodiazepines allosterically bind to
`the receptor at a different location than GABA
`does and enhance the chloride channelÕs conduc-
`tance by increasing the frequency of gated chan-
`nel opening (6, 7, 10–12).
`In the search for BZD site ligands with higher
`therapeutic selectivity and a more favorable safety
`profile, GABAA receptor subtypes have long been
`considered promising targets (13). The pharmaco-
`logic relevance of GABAA receptor subtypes has
`been identified using a gene knock-in strategy in
`rodents. Based on in vivo point mutations,
`a-1-GABAA receptors have been found to mediate
`sedation and anterograde amnesia and to par-
`tially mediate anticonvulsant activity, whereas
`a-2-GABAA receptors mediate anxiolysis (14, 15).
`The basic chemical structure of BZDs is formed
`from the fusion of a benzene ring and a seven-
`membered diazepine ring (16) (Fig. 1). Clobazam is
`an exception with its 1-5-BZD structure (17). The
`common chemical structure of the BZDs accounts
`for their similar mechanisms of action.
`In pharmacologic terms, BZD potency refers to
`the in vivo affinity of
`the drug (or its active
`metabolites) for its receptor (18). Benzodiazepines
`are classified as low, medium (e.g. clorazepate and
`diazepam) or high (e.g. clonazepam and loraze-
`pam) potency (18, 19).
`
`Benzodiazepine pharmacokinetics
`
`Benzodiazepines have differences in their physio-
`chemical properties, most notably lipid solubility,
`which influence their
`rate of absorption and
`diffusion into tissue compartments and their phar-
`macokinetics. Each BZD has a unique pharmaco-
`kinetic profile that must be considered when the
`optimal agent is selected for a particular patient
`and condition. Key factors to consider include
`
`R1
`
`N
`
`O
`
`R2
`
`N
`
`R3
`
`ortho
`
`R7
`
`Figure 1. General chemical structure of 1,4- benzodiazepines.
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`route of administration, rate and extent of absorp-
`tion, metabolism, formation of active metabolites,
`elimination and drug interactions (20).
`
`Absorption and distribution
`
`When orally administered, most BZDs are exten-
`sively and rapidly absorbed, with bioavailabilities
`varying from 80% to 100% and times to peak
`concentration ranging from minutes to several hours
`(Table 1). Midazolam is an exception, with low oral
`bioavailability due to metabolism by cytochrome
`P-450 (CYP) enzyme 3A5 in intestinal epithelial
`tissue, which can reduce by up to 50% the fraction of
`the dose reaching the bloodstream (24). Benzodiaze-
`pines
`cross
`the blood–brain barrier
`rapidly,
`although the diffusion rate into the brain varies by
`drug and is largely determined by lipophilicity (21).
`The faster the diffusion rate, the earlier is the onset of
`pharmacodynamic effects. Rapid entry of BZDs
`into the CNS and highly perfused tissues is consis-
`tent with their short distribution half-lives (21, 25).
`Following rapid uptake, BZDs redistribute into less
`well-perfused tissues; the rate of redistribution is the
`fastest for the most lipid-soluble drugs (25). After an
`intravenous (i.v.) BZD administration, BZD phar-
`macokinetics can be characterized by a multicom-
`partmental mathematical model, with the first phase
`being distribution, followed by a longer elimination
`phase. Benzodiazepines also have large volumes of
`distribution, are highly bound to plasma proteins
`(Table 1) and readily cross into the placenta and
`breast milk (25).
`
`Table 1 Summary of absorption and distribution pharmacokinetics of selected
`BZDs
`
`Drug
`
`F (%)
`
`Tmax
`
`Clobazam
`Clonazepam
`Clorazepateb
`
`Diazepam
`
`Lorazepam
`
`Midazolam
`
`87
`>80
`PO: 100
`IM: 91
`PO: 100
`R: 90 (23)
`
`PO: 99
`IM: 96
`SL: 94
`PO: 40
`IM: 100
`
`1.3–1.7 h
`1–4 h
`PO: 0.5–2 h
`IM: 2.7–11 h
`PO: 30–90 min
`IM: 30–60 min
`R: 10–45 min
`PO: 2.4 h
`IM: 1.2 h
`SL: 2.3 h
`PO: 0.5–0.97 h
`IM: 0.24–0.51 h
`
`Protein
`binding
`(% bound)
`
`Distribution
`half-lifea
`(min)
`
`Vd (l ⁄ kg)
`
`82–90
`86
`96–98
`
`NA
`30 min (21)
`6–29 min (22)
`
`0.87–1.83
`1.5–4.4
`0.7–2.2
`
`96–99
`
`2–13 min (21)
`
`0.95–2.0
`
`93.2
`
`<11 min (21)
`
`0.85–1.5
`
`96
`
`4–19 min (21)
`
`0.7–1.7
`
`Values refer to adults receiving monotherapy and are from Anderson and Miller
`(24) unless otherwise specified. BZD, benzodiazepine; F, bioavailability; Tmax, time
`to maximum concentration; Vd, volume of distribution; NA, not applicable; PO, oral;
`IM, intramuscular; R, rectal; SL, sublingual.
`aAfter intravenous administration.
`bPharmacokinetics for N-desmethyldiazepam after administration of clorazepate.
`
`Benzodiazepines in the treatment of epilepsy
`
`Metabolism and elimination
`
`Benzodiazepines differ in their rates of elimination
`and the formation of pharmacologically active
`metabolites (Table 2). The elimination half-life
`(t1 ⁄ 2) of a BZD or of its active metabolite is used
`to categorize BZD duration of effect: short acting
`(<10 h;
`lorazepam, midazolam),
`intermediate
`acting (10–24 h; clonazepam) or
`long acting
`(>24 h; clobazam, clorazepate and diazepam) (43).
`Benzodiazepine metabolism is primarily cata-
`lyzed by CYP-dependent hydroxylation, demeth-
`ylation and nitroreduction (26, 44, 45). The CYP
`isoenzymes catalyzing these reactions include 3A4,
`3A5, 2B6, 2C9 and 2C19 (Tables 2 and 3). Uridine
`diphosphate
`glucuronosyltransferase
`is
`also
`involved in the conjugation of some BZDs (Table 3).
`Several BZDs have active metabolites. Diazepam
`and clorazepate are metabolized into the long-acting
`metabolite DMD (56). With multiple doses, the
`pharmacologic and toxic effects of diazepam are
`attributable to the parent drug, DMD, and other
`minor active metabolites (i.e. temazepam and oxaz-
`epam) (24). By contrast, clorazepate undergoes rapid
`and complete chemical conversion to DMD in the
`gastrointestinal tract; its pharmacologic effects are
`largely due to DMD (24, 56). N-Desmethyldiazepam
`undergoes glucuronidation to form a glucuronide
`conjugate (25%) and is hydroxylated (50%) by CYP
`2C19 and CYP 3A4 to form oxazepam (24, 37).
`Approximately
`5–9% of DMD is
`excreted
`unchanged in the urine (24). The t1 ⁄ 2 of DMD
`ranges widely from 20 to 179 h (24, 33, 34, 38).
`Other BZDs also have pharmacologically active
`metabolites. Clobazam is demethylated into an
`(N-desmethylclobazam)
`active metabolite
`(27).
`Midazolam is rapidly converted by CYP 3A4 and
`CYP 3A5 to 1-hydroxymidazolam, which contrib-
`utes approximately 10% to the biologic activity of
`its parent drug (24, 41). Clonazepam and loraze-
`pam undergo extensive metabolism, but no active
`metabolites are formed (18, 24).
`
`Effects of pharmacokinetics and pharmacodynamics
`on BZD use – The differences in BZD pharmacoki-
`netics and pharmacodynamics must be considered
`in order to use these drugs safely and effectively.
`Equivalent doses of BZDs differ as much as 20-fold
`because of differences in potency (57). The intensity
`of single-dose effects may vary, even if equipotent
`doses are used, because of varying oral absorption
`rates (58). Duration of action should be considered
`when choosing a BZD. When maintenance therapy
`is required (e.g. epilepsy and anxiety), long-acting
`BZDs are preferred because of their prolonged t1 ⁄ 2,
`as effective drug concentrations can be maintained
`
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`Riss et al.
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`Table 2 Summary of metabolism and elimination pharmacokinetics of selected BZDs
`
`Drug
`
`Clobazam
`Clonazepam
`
`Clorazepate
`
`Diazepam
`
`Lorazepam
`Midazolam
`
`Primary metabolic pathway
`
`Active metabolites
`
`Elimination half-life of
`parent druga (h)
`
`Elimination half-life of
`active metabolites (h)
`
`Demethylation (26)
`Nitroreduction (CYP 3A4),
`acetylation (NAT), hydroxylation (29–31)
`Decarboxylation, glucuronidation,
`hydroxylation (CYP 2C19 and 3A4) (24)
`Demethylation (CYP 2C9, 2C19, 2B6, 3A4,
`and 3A5), hydroxylation (CYP 3A4 and 2C19),
`glucuronidation (24, 35, 36)
`Glucuronidation (24)
`Hydroxylation (CYP 3A4 and 3A5) (25, 41, 42)
`
`N-desmethylclobazam (27)
`NA
`
`10–30 (28)
`19–60 (32)
`
`36–46 (28)
`NA
`
`DMD (major), oxazepam (minor) (24)
`
`NA
`
`DMD (major), oxazepam (minor),
`temazepam (minor) (24, 35, 37)
`
`21–70 (23, 38)
`
`NA
`1-hydroxymidazolam (minor) (24)
`
`7–26 (39, 40)
`1–4 (24)
`
`20–160 (24, 33, 34)
`Oxazepam: 6–24 (18)
`DMD: 49–179 (33, 38)
`Oxazepam: 6–24 (18)
`Temazepam: 8–24 (18)
`NA
`1 (24)
`
`BZD, benzodiazepine; CYP, cytochrome P-450; NAT, N-acetyltransferase; NA, not applicable; DMD, N- desmethyldiazepam.
`aHealthy subjects.
`
`Table 3 Enzyme-mediated BZD metabolism and drug interactions
`
`Enzyme
`associated
`with
`metabolism
`
`BZD
`substrates
`
`CYP 2C19
`
`Diazepam (46)
`
`CYP 3A4
`
`Clonazepam (29)
`
`Diazepam (46)
`Midazolam (46)
`
`UGT
`
`Lorazepam (53)
`Oxazepam (54)
`
`Inhibitors
`
`Inducers
`
`Fluvoxamine (46)
`MHD (weak) (47)
`Omeprazole (46)
`Oxcarbazepine (46)
`Ticlopidine (46)
`Topiramate (46)
`Azole antifungals
`(e.g. ketoconazole) (46)
`Cimetidine (46)
`Clarithromycin (46)
`Diltiazem (46)
`Erythromycin (46)
`Fluoxetine (51)
`Grapefruit juice (46)
`HIV protease
`inhibitor (46)
`Nefazodone (46)
`Sertraline (51)
`Valproate (55)
`
`Dexamethasone (48)
`Phenobarbital (48)
`Phenytoin (49)
`Rifampin (46)
`St JohnÕs wort (50)
`
`Carbamazepine (46)
`
`Phenobarbital (48)
`Phenytoin (46)
`Rifabutin (46)
`Rifampin (52)
`Rifapentine (51)
`St JohnÕs wort (50)
`
`Carbamazepine (55)
`Lamotrigine (weak) (55)
`Phenobarbital (55)
`Phenytoin (55)
`Rifampin (52)
`
`BZD, benzodiazepine; CYP, cytochrome P-450; MHD, monohydroxy derivative; HIV,
`human immunodeficiency virus; UGT, uridine diphosphate glucuronosyltransferase.
`
`without the need for frequent dosing (56). Short-
`acting BZDs are preferred for intermittent hyp-
`notic therapy, when the duration of action of the
`drug should be restricted to night-time, allowing
`patients
`to awaken feeling refreshed, without
`hangover effects (56).
`
`Drug–drug interactions
`
`Benzodiazepines interact with other drugs such as
`certain antidepressants, AEDs (e.g. phenobarbital,
`
`72
`
`phenytoin and carbamazepine), sedative antihista-
`mines, opiates, antipsychotics and alcohol (44, 57,
`59), which may result in additive sedative effects.
`As discussed earlier, BZD metabolism is com-
`plex and largely catalyzed by CYP isoenzymes.
`Consequently, there is potential for interactions
`between BZDs and drugs that induce or inhibit
`CYP isoenzymes. The clinical importance of these
`interactions depends on the net effect of inhibition
`or induction on the metabolic pathway of a
`particular BZD. For example,
`inhibition of a
`minor pathway may have little impact on drug
`concentration, whereas
`inhibition of a major
`pathway may result in enhanced clinical effect or
`toxicity. By contrast, addition of an enzyme-
`inducing drug that affects even a relatively minor
`pathway may lead to a clinically important reduc-
`tion in plasma BZD concentration. For BZDs with
`active metabolites, the addition of an inhibitor or
`inducer may affect only the parent drug, only the
`metabolite, or both. Clinicians should exercise
`particular caution when using BZDs with selective
`serotonin reuptake inhibitors, cimetidine, macro-
`lide antibiotics and antimycotics; these drugs may
`inhibit reactions catalyzed by certain CYP isoen-
`zymes and, therefore, inhibit the metabolism of
`many BZDs, which results in increased plasma
`BZD concentrations
`(44). Conversely, potent
`enzyme inducers (e.g. phenytoin, phenobarbital
`and carbamazepine) substantially increase clear-
`ance and reduce the t1 ⁄ 2 of certain BZDs (44). For
`a detailed review of pharmacokinetic drug interac-
`tions involving BZDs, see Tanaka (44).
`the
`Oral contraceptive steroids may inhibit
`metabolism of some BZDs that undergo oxidative
`metabolism or nitroreduction and accelerate
`the metabolism of some BZDs that are conjugated.
`Interactions between BZDs and oral contraceptives
`are described in detail by Back and Orme (60).
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`Special populations
`
`Special formulations of BZDs
`
`Benzodiazepines in the treatment of epilepsy
`
`Elderly patients – Pharmacokinetics in older indi-
`viduals differ from those in younger individuals
`because of age-related changes in physiology and the
`likelihood of concurrent diseases. Elderly individu-
`als often have variable drug absorption, decreased
`plasma protein–drug binding due to lower albumin
`concentrations, and reduced hepatic and renal
`clearance (61). Additionally, many elderly individ-
`uals take multiple medications, which increase their
`risk of drug–drug interactions. Therefore, treatment
`of the elderly can be challenging.
`Increased sensitivity of older patients to BZDs is
`partly due to reduced drug metabolism (when
`compared with younger adults), which can result in
`drug accumulation (62). Furthermore, BZD phar-
`macologic effects appear to be greater in elderly
`patients than in younger patients even at similar
`plasma BZD concentrations (63, 64), possibly
`because of age-related changes in drug–receptor
`interactions, post-receptor mechanisms and organ
`function. When a BZD is prescribed for an elderly
`patient, the initial maintenance dose should be half
`that recommended for younger adults (57), and
`BZD use should be only short term (limited to
`2 weeks) (65). A short-acting BZD may be prefer-
`able for treating an elderly patient because such a
`drug is better tolerated than is a BZD or BZD
`active metabolite with a long t1 ⁄ 2 (64).
`
`Pediatric patients – Limited information is available
`regarding BZD absorption in children. Often,
`before children are administered medications, the
`tablet is crushed or the capsule is opened, and the
`contents are mixed with food or drink. Food and
`beverages may affect BZD bioavailability, but
`studies investigating this issue in children are
`lacking.
`Drug metabolism is variable in children and
`depends on the biotransformation pathway. Cyto-
`chrome P-450-catalyzed metabolism tends to be
`low at birth, but exceeds adult values by age
`2–3 years; thereafter, CYP-catalyzed metabolism
`decreases, reaching adult levels around puberty
`(66). Metabolism via glucuronidation tends to be
`low in neonates, reaching adult
`levels by age
`3–4 years (66). In neonates, the t1 ⁄ 2 of clorazepate
`is prolonged and clearance is decreased (67).
`Infants have reduced hydroxylation metabolism,
`which results in a decreased clearance of diazepam
`(68). The t1 ⁄ 2 of midazolam is shorter in children
`than in adults: 0.79–2.83 h in children (69) vs 1.36–
`4 h in adults (24). Clinicians should consider how
`patient age may affect BZD clearance, because
`clearance will affect BZD dosing.
`
`can help
`Extended-release drug formulations
`patients with epilepsy achieve their primary treat-
`ment goals of controlling seizures while reducing
`side effects by minimizing fluctuations in drug
`concentration and by improving compliance.
`Extended-release formulations may also improve
`quality of
`life and patient
`satisfaction with
`treatment, in part by simplifying dosage regimens
`(70). Currently, clorazepate is the only BZD
`available in both a sustained-release, single-dose
`(TranxeneÒ-SD, Ovation Pharmaceuticals, Deer-
`field, IL, USA) formulation (11.25- and 22.5-mg
`tablets) and an immediate-release formulation that
`requires multiple doses per day (TranxeneÒ T-Tab;
`3.75-, 7.5- and 15-mg tablets) that is approved in
`the USA for the treatment of seizures. Some BZDs
`are also available as oral liquids [diazepam (Diaz-
`epam Intensol; 5 mg ⁄ ml), lorazepam (Lorazepam
`Intensol; 2 mg ⁄ ml) and midazolam (generic only;
`2 mg ⁄ ml)], disintegrating
`tablets
`[clonazepam
`(KlonopinÒ Wafer; Roche
`Pharmaceuticals,
`Nutley, NJ, USA; 0.125-, 0.25-, 0.5-, 1- and 2-mg
`[diazepam (DiastatÒ
`tablets)] or a rectal gel
`AcuDial; Valeant Pharmaceuticals International,
`Costa Mesa, CA, USA; 2.5-, 10- and 20-mg
`delivery systems)].
`
`Effect of extended-release formulations on plasma
`BZD concentrations: pharmacokinetic
`simulations
`with clorazepate – Our group has performed simu-
`lation studies of plasma DMD concentrations over
`time to investigate differences between clorazepate
`formulations and to characterize the effect of
`missed doses with or without replacement doses
`under
`steady-state conditions when using the
`sustained-release and immediate-release formula-
`tions (71). These simulations were briefly described
`by Kaplan and DuPont (72), but detailed results
`are reported herein. The following simulations
`were performed for both formulations using
`WinNonlinÒ (Pharsight Corporation, version 4.1:
`Mountain View, CA, USA) software and a two-
`compartment, first-order, oral-absorption pharma-
`cokinetic model: (1) steady-state conditions, (2)
`missed dose(s) without replacement and (3) missed
`dose(s) with replacement at the next scheduled
`dose. The following dosing schedules for the
`sustained-release and immediate-release formula-
`tions were entered to attain steady-state conditions
`(>7 days): clorazepate sustained-release 22.5 mg –
`one tablet orally every 24 h for 20 days; and
`clorazepate immediate-release 7.5 mg – one tablet
`orally three times daily (given 6 h apart)
`for
`20 days. The resulting simulated plasma DMD
`
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`

`concentrations over time are depicted in Figs 2–4.
`The mean steady-state plasma DMD concentration
`was approximately 0.71 lg ⁄ ml for the immediate-
`release formulation and 0.73 lg ⁄ ml for the sus-
`tained-release formulation. The time to maximum
`concentration was 2.43 and 9.20 h for the imme-
`diate-release and sustained-release formulations
`respectively. Table 4 shows the effects of missed
`doses on plasma DMD concentrations. When a
`missed dayÕs dose of the immediate-release formu-
`lation was simulated, peak-to-trough differences
`(compared with steady
`state)
`increased by
`0.05 lg ⁄ ml
`(38.5%) with no dose replacement
`and increased by 0.29 lg ⁄ ml
`(223.1%) with
`replacement of the missed doses (Table 4). How-
`ever, when a missed dayÕs dose of the sustained-
`release formulation was simulated, peak-to-trough
`differences increased by 0.01 lg ⁄ ml (5.9%) with no
`dose replacement and increased by 0.24 lg ⁄ ml
`(141.2%) with replacement of the missed dose
`(Table 4).
`Despite the long half-life of DMD, a missed
`dayÕs dosing can result in altered peak-to-trough
`concentration ratios. Overall,
`the differences
`between peak and trough plasma DMD concen-
`trations after a missed daily dose of clorazepate
`increased more with the immediate-release formu-
`lation than with the sustained-release formulation
`(Table 4). There was little difference between the
`two formulations in peak and trough concentra-
`tions following a missed dayÕs dose. Although the
`effect was modest,
`the sustained-release tablet
`maintained higher trough concentrations after a
`missed daily dose and replacement of the missed
`dose. This effect may prevent breakthrough sei-
`zures in some patients. Additionally, when a
`missed daily dose was replaced, the sustained-
`release formulation resulted in a smaller change in
`peak concentrations, which may reduce the risk of
`drug toxicity.
`
`Use of benzodiazepines in epilepsy
`
`Efficacy
`
`Benzodiazepines are among the most useful AEDs
`available for treating status epilepticus and acute
`repetitive seizures and for febrile seizure prophy-
`laxis. Benzodiazepines were used in epilepsy man-
`agement as early as 1965, when Gastaut et al. (73,
`74) administered i.v. diazepam to treat status
`epilepticus. Since then, several other BZDs have
`been used for a variety of
`seizure disorders
`(Table 5).
`Several randomized controlled trials support the
`use of BZDs (particularly diazepam and loraze-
`
`Riss et al.
`
`0
`
`50
`
`100
`
`150
`
`300
`200
`250
`Time (h)
`
`350
`
`400
`
`450
`
`500
`
`1.0
`
`0.8
`
`0.6
`
`0.4
`
`0.2
`
`0.0
`
`Predicted DMD concentration (µg/ml)
`
`Figure 2. Simulated plasma N-desmethyldiazepam (DMD)
`concentration over time for immediate-release clorazepate
`(solid line, 7.5 mg given every 6 h for three daily doses) and
`sustained-release clorazepate (dashed line, 22.5 mg once daily)
`with no missed doses.
`
`Missed dose
`
`Missed doses
`
`0
`
`50
`
`100
`
`150
`
`200
`
`250
`
`300
`
`350
`
`400
`
`450
`
`500
`
`Time (h)
`
`1.0
`
`0.8
`
`0.6
`
`0.4
`
`0.2
`
`0.0
`
`Predicted DMD concentration (µg/ml)
`
`Figure 3. Simulated plasma N-desmethyldiazepam (DMD)
`concentration over time for immediate-release clorazepate
`(solid line, 7.5 mg given every 6 h for three daily doses) and
`sustained-release clorazepate (dashed line, 22.5 mg once daily),
`missed daily dose(s) without replacement.
`
`Missed dose
`
`Replaced dose
`Replaced doses
`
`Missed
`doses
`
`0
`
`50
`
`100
`
`150
`
`200
`
`250
`
`300
`
`350
`
`400
`
`450
`
`500
`
`Time (h)
`
`1.0
`
`0.8
`
`0.6
`
`0.4
`
`0.2
`
`0.0
`
`Predicted DMD concentration (µg/ml)
`
`Figure 4. Simulated plasma N-desmethyldiazepam (DMD)
`concentration over time for immediate-release clorazepate
`(solid line, 7.5 mg given every 6 h for three daily doses) and
`sustained-release clorazepate (dashed line, 22.5 mg once daily),
`missed daily dose(s) replaced at next dayÕs dose.
`
`74
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`

`Benzodiazepines in the treatment of epilepsy
`
`Table 4 Effects of missed doses on simulated plasma DMD concentrations (71)
`
`Clorazepate sustained-release
`
`Clorazepate immediate-release
`
`Formulation
`
`Simulation schemea
`
`Peak ⁄ trough differenceb at steady state (lg ⁄ ml)
`Peak ⁄ trough differenceb after missed dose(s) (lg ⁄ ml)
`Change in peak plasma DMD concentrations (%)
`Change in trough plasma DMD concentrations (%)
`
`1
`
`0.17
`NA
`NA
`NA
`
`2
`
`NA
`0.18
`)29.6
`)44.1
`
`3
`
`NA
`0.41
`6.0
`)41.9
`
`1
`
`0.13
`NA
`NA
`NA
`
`2
`
`NA
`0.18
`)27.1
`)48.8
`
`3
`
`NA
`0.42
`9.6
`)48.8
`
`DMD, N-desmethyldiazepam; NA, not applicable.
`aSimulation scheme: 1 = no missed doses; 2 = missed daily dose(s) without replacement; 3 = missed daily dose(s) with replacement.
`bDifference between maximum plasma DMD concentration and minimum plasma DMD concentration.
`
`Table 5 Recommended clinical uses of benzodiazepines
`
`Drug
`
`Trade Name
`
`Generic availability
`
`Product-labeled uses (75)
`
`Common uses in epilepsy (76)
`
`Clobazam
`
`Frisium
`
`Clonazepam
`
`Klonopin
`
`Clorazepate
`
`Diazepam
`
`Tranxene T-Tab
`Tranxene-SD
`Valium
`
`Lorazepam
`
`Midazolam
`
`Ativan
`
`Versed
`
`NA
`
`Yes
`
`Yes
`
`Yes
`
`Yes
`
`Yes
`
`Not FDA approved
`
`Panic disorder, epileptic
`seizures (alone or adjunct)
`
`Anxiety, alcohol withdrawal,
`adjunctive treatment of partial seizures
`Anxiety, alcohol withdrawal,
`muscle relaxant, epileptic seizures
`
`Anxiety, pre-anesthetic to induce amnesia,
`antiemetic adjunct, status epilepticus
`Anesthesia, preoperative and procedural
`sedation
`
`First-line adjunctive treatment for treatment-resistant
`partial and generalized seizures, intermittent
`therapy and non-convulsive status epilepticus
`Second-line adjunctive treatment for partial and
`generalized (particularly absence and myoclonic)
`seizures, early status epilepticus and
`Lennox–Gastaut syndrome; second-line
`treatment of status epilepticus
`Adjunctive treatment of partial seizures (75)
`
`First-line treatment for early status epilepticus;
`second-line therapy for established
`status epilepticus; treatment of
`non-convulsive status epilepticus;
`intermittent prophylactic therapy for
`febrile seizures; and at-home treatment of ARS
`First-line treatment for early status epilepticus
`and out-of-hospital status epilepticus
`Second-line therapy for early status epilepticus
`
`NA, not applicable; FDA, US Food and Drug Administration; ARS, acute repetitive seizures.
`
`pam) as initial drug therapy in patients with status
`epilepticus (77–80). Intermittent use of BZDs is
`especially suitable for patients with clusters of
`repetitive seizures (81). Fewer studies have evalu-
`ated the clinical efficacy of BZDs in chronic
`epilepsy. Nevertheless, BZDs are useful as adjunc-
`tive agents in treating certain patients with both
`partial and primary generalized seizures
`(81).
`Benzodiazepines are versatile drugs that can be
`employed in a variety of clinical settings because of
`their broad spectrum of activity and multiple
`formulations and because they can be administered
`by several routes (81).
`
`Diazepam – Diazepam is a drug of first choice for
`treatment of early status epilepticus and acute
`repetitive seizures and for febrile seizure prophy-
`laxis. It can be administered as an i.v. bolus, as a
`continuous infusion, or rectally, which enhances its
`
`utility in managing seizure emergencies. Four
`randomized controlled trials support diazepam as
`a drug of first choice for managing status epilep-
`ticus (77–80). Success rates of i.v. diazepam for
`treating status epilepticus vary. In a randomized
`double-blind study comparing diazepam and
`lorazepam, Leppik et al. (80) found that 76% of
`status epilepticus episodes (25 of 33) were termi-
`nated by one or two diazepam doses (5 mg ⁄ min).
`In a randomized, non-blinded trial of patients
`>15 years of age with status epilepticus, Shaner
`et al. (78) reported that seizures were aborted in
`<10 min in 55.6% of patients (10 of 18) treated
`diazepam (2 mg ⁄ min)
`with
`and
`phenytoin
`(40 mg ⁄ min). A randomized, double-blind, multi-
`center Veterans Affairs cooperative study was
`designed to compare the effectiveness of
`four
`treatments for overt or subtle status epilepticus
`(79). Three hundred eighty-four patients with overt
`
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`
`

`

`Riss et al.
`
`status epilepticus and 134 patients with subtle
`status epilepticus were randomly assigned to
`receive either diazepam (0.15 mg ⁄ kg)
`followed
`by phenytoin (18 mg ⁄ kg), lorazepam (0.1 mg ⁄ kg)
`(15 mg ⁄ kg)
`alone,
`phenobarbital
`alone
`or
`phenytoin (18 mg ⁄ kg) alone. Treatment with diaz-
`epam plus phenytoin was successful in 55.8% of
`patients (53 of 95) with overt status epilepticus and
`8.3% of patients (three of 36) with subtle status
`epilepticus (79). Alldredge et al. (77) conducted a
`randomized double-blind trial to determine the
`effectiveness of
`i.v. diazepam,
`lorazepam and
`placebo on status epilepticus when the drugs were
`administered by paramedics before patients arrived
`at the hospital. They found that status epilepticus
`was terminated by the time of arrival
`in the
`emergency department in 42.6% of the 68 patients
`treated with one or two 5-mg doses of
`i.v.
`diazepam (infused over 1–2 min). Limited pub-
`lished data indicate that continuous i.v. infusions
`of diazepam are safe and effective (82–84).
`Use of i.v. diazepam can result in seizure relapse
`within 2 h of a single injection in approximately
`50% of patients (76). Therefore, multiple injections
`or continuous