Pharmacodynamic and pharmacokinetic characteristics of intravenous drugs in status epilepticus


Address correspondence to Meir Bialer, PhD, MBA, David H. Eisenberg Professor of Pharmacy, Department of Pharmaceutics, School of Pharmacy, Faculty of Medicine, Ein Karem, The Hebrew University of Jerusalem, Jerusalem 91120, Israel. E-mail:

Antiepileptic drugs (AEDs) are first developed as tablets or solid oral dosage forms, since a new molecular entity with a small molecular weight (<1,000 Da) in which epilepsy is its primary indication must be efficacious following oral dosing before it can be further developed in nonoral formulations. Subsequently, new AEDs, primarily those that are water soluble, are then formulated as intravenous or parenteral preparations and tested or utilized for status epilepticus (SE).

Intravenous administration of AEDs produces the most rapid onset of action, as it is delivered directly into the bloodstream and immediately produces maximum plasma concentration (C0 = Cmax). In addition to its therapeutic value, intravenous administration bypasses absorption and focuses on the disposition (distribution plus elimination) and, therefore, is essential in investigating the pharmacokinetics (PK) or clinical pharmacology of drugs (Bialer, 2007). Consequently due to its direct delivery of drugs to the blood, intravenous injection or infusion is the reference route for absolute bioavailability calculations.

Most AEDs exhibit linear (concentration-independent) PK within their clinically relevant doses, namely, their plasma concentrations increase or decrease proportionally to dose. Therefore, the drug’s major PK parameters: clearance (CL), apparent volume of distribution (V), and half-life (t1/2) are not affected by the dose, rate or extent of absorption, or mode of administration (Bialer & Cloyd, 1995). Because absorption is dependent on the drug and the drug product (formulation), changes in route of administration or in the parenteral (extravascular) formulation affect only the extent and rate of absorption. In contrast, the three major PK parameters (CL, V, and t1/2) are intrinsic properties of the AED or the active entity that do not change between single and multiple dosing and remain constant regardless of the route of administration, as long as the drug PK is linear.

The preferred parenteral preparation is an aqueous solution that usually distributes rapidly from the administration site. Hydroalcoholic, oily, or suspension vehicles may be painful following intramuscular or subcutaneous administration, result in slow and sustained absorption, and unlike aqueous injections cannot be diluted for infusions. Therefore, nonaqueous vehicles may cause adverse reactions. The four major established AEDs—phenobarbital (PB), phenytoin (PHT), carbamazepine (CBZ), and valproic acid (VPA) per se—are water-insoluble drugs. The same is true for the two benzodiazepines, diazepam (DZP) and lorazepam (LZP), which are available in parenteral preparations and are the first drugs of choice for treatment of SE.

DZP injection contains 0.5% DZP in a mixture of 40% propylene glycol, 10% alcohol, and 50% water for injection at pH 6.2–7. DZP has a complete oral bioavailability (F = 100 ± 14%), low total clearance (CL) that is mainly metabolic or hepatic (CL = 0.38 ± 0.06 ml/min per kg), a volume of distribution (V) of 1.1 ± 0.3 L/kg, and a long half-life (t1/2) of 43 ± 13 h (Greenblatt et al., 1980; Freedman et al., 1992). DZP is extensively metabolized to several active metabolites including desmethyldiazepam (DMD), temazepam (3-OH-DZP), and oxazepam (3-OH-DMD), which is a DZP secondary metabolite formed from either DMD or temazepam by CYP3A4 and CYP2C19, respectively (Anderson et al., 1994). The formation of DMD is mediated by CYP2C19 (major) and CYP3A4, and due to its very long half-life (t1/2 = 100–150 h) DMD accumulates in blood to concentrations 7-fold higher than those of DZP (Anderson & Miller, 2002).

LZP injection contains 0.2% LZP in a mixture of 40% propylene glycol, 10% alcohol, and 50% water for injection. LZR has a complete oral bioavailability (F = 93 ± 10%), low CL that is mainly metabolic or hepatic (CL = 1.1 ± 0.4 ml/min per kg), and a V of 1.3 ± 0.2 L/kg. LZP has a half-life shorter than that of DZP (t1/2 = 14 ± 15 h) due to its 3-fold higher CL (Greenblatt, 1981; Anderson & Miller, 2002). Unlike DZP, the metabolism of which is mediated by CYP2C19 and CYP3A4, LZP is extensively metabolized by the hepatic UDP glucuronyl transferases (UGTs) to LZP-3-O-glucuronide (inactive).

Midazolam (MDZ), a third short-acting benzodiazepine, is available in a parenteral aqueous preparation and is used for treatment of SE. MDZ injection contains 0.5% MDZ hydrochloride in water for injection (buffered to pH = 3.3–3.5). MDZ undergoes a facile 1,4-benzoidiapzpine ring-opening in an acidic aqueous solution to form a benzophenone derivative. Its reverse cyclization reaction to MDZ occurred in vivo at physiologic pH (pH = 7.4) and in vitro when an acidic solution was neutralized (Garzone & Kroboth, 1989; Lowenstein & Cloyd, 2007). MDZ has a partial oral bioavailability (F = 44 ± 17%) due to extensive first-pass metabolism by intestinal and hepatic CYP3A4. The bioavailability appears to be dose-dependent: 35–67% at 15 mg, 28–36% at 7.5 mg, and 12–47% at 2 mg oral dose, possibly due to saturable first-pass intestinal metabolism (Thummel et al., 1996). MDZ has a high total (metabolic) CL (CL = 6.6 ± 1.8 ml/min per kg), a V of 1.1 ± 0.6 L/kg, and short half-life (t1/2 = 1.1 ± 0.6 h). The following characteristics allow for the preparation of commercially stable water-soluble MDZ injections: (1) short t1/2 due to the methyl at position 1 on the imidazole ring that undergoes CYP-mediated oxidation more rapidly than the methylene group at position 4 of the classical benzodiazepine nucleus, and (2) enhanced potency due to its high affinity to the benzodiazepine receptors (Garzone & Kroboth, 1989). MDZ is exclusively metabolized by CYP3A4 and, therefore, has been used as a probe for this CYP (Thummel et al., 1996).

The most common treatment protocols for SE specify DZP or LZP as the first drug therapy, followed by PHT or fosphenytoin (FOS) as a second-line therapy, and then phenobarbital (mainly) or VPA or general anesthetic (Lowenstein, 2006). The goals of pharmacologic therapy for SE are to terminate seizures early and prevent recurrence. Two recent large clinical studies have shown the benefit of early administration of benzodiazepines to control SE and then FOS (Claassen et al., 2003; Holtkamp et al., 2003). Claassen et al. (2002) also conducted a meta-analysis on the advantages and disadvantages of PB, MDZ, and propofol, which showed that PB appears to be superior in effectively controlling refractory SE. When administered intravenously, all three benzodiazepines rapidly enter the central nervous system (CNS) and the resulting onset of effect occurs within 1–5 min. However, DZP and MDZ quickly redistribute to muscle and fat tissue because their lipophilicity (assessed by the octanol/water partitioning) is 4–6 times higher than that of LZP (Lowenstein & Cloyd, 2007). However, DZP redistributes rapidly to peripheral fats, and consequently its clinical effectiveness is limited to 20–30 min. Therefore, DZP treatment of SE needs to be followed with a second drug such as LZP that has a more favorable pharmacokinetic profile than DZP and duration of action exceeding 12 h.

PB is a weak acid (pKa = 7.3) that is sparingly soluble in water (1 mg/ml). PB sodium salt (PB-Na) has better water solubility than PB per se (free acid) and consequently has been utilized in PB parenteral preparations. Nevertheless, a PB injection is not an aqueous solution but contains 20% PB-Na in a mixture of 90% propylene glycol and 10% water at pH = 10–11. PB has a complete oral bioavailability (F = 100 ± 11%), very low total clearance (CL = 0.06 ± 0.01 ml/min per kg) that is 75% (hepatic) metabolic and 25% renal, a volume of distribution less than the total body water (V = 0.54 ± 0.03 L/kg), and a long half-life (t1/2 = 99 ± 18 h) (Browne et al., 1985; Anderson, 2002). PB is mainly metabolized to two inactive primary metabolites: p-hydroxy-PB, which is excreted in the urine as free and glucuronide conjugate, and an N-glucoside conjugate of PB (Anderson, 2002). PB’s long half-life is a drawback in terms of adverse effects.

The differences between aqueous and hydroalcoholic parenteral preparations of AEDs are best illustrated by the development of FOS. FOS is a disodium phosphate ester of 3-hydroxymethyl of phenytoin developed as a replacement for standard injectable phenytoin sodium. The water solubility of FOS is 75,000 mg/L versus only 20 mg/L for phenytoin sodium. Consequently, FOS was designed and developed as an aqueous parenteral prodrug to phenytoin to avoid the local complications associated with parenteral phenytoin such as intravenous fluid incompatibilities, patient discomfort, vein irritation/tissue damage, and muscle necrosis after intramuscular administration. The parenteral preparation of phenytoin sodium (50 mg/ml) is a hydroalcoholic mixture of 40% propylene glycol, 10% alcohol, and 50% water, with the pH adjusted to 12. FOS is administered by either an intravenous or intramuscular route and is rapidly and completely converted enzymatically to phenytoin (conversion t1/2 = 3 min in dogs, 1 min in rats) (Browne & LeDuc, 1995). Admixtures of FOS solutions diluted to phenytoin concentrations of 1, 8, and 20 mg/ml in 0.9% NaCl, D5W, and other intravenous fluids were physically compatible and chemically stable. Clinical studies in adults and children indicate that intramuscular and intravenous forms of FOS were well tolerated, safe, and rapidly and completely converted to phenytoin (Bialer et al., 2002). Phenytoin or its parenteral prodrug FOS is also utilized in the treatment of SE, with a loading dose of 1 g or 20 mg/kg administered at a maximum rate of 50 mg/min. In the absence of a clinical effect, an additional 10 mg/kg is given because many patients may require PHT plasma levels of 25–30 mg/L to achieve seizure control. The most common side effects of PHT intravenous dosing are cardiovascular including hypotension and QT prolongation. PHT has been shown to be effective for the treatment of SE, but it is considered a third-line drug in the algorithms designed to treat SE because of its serious adverse effect profile.

Sodium valproate injection (Depacon, Abbott, Abbott Park, IL, U.S.A.) was approved in the United States in 1996 for intravenous use in patients with epilepsy for whom oral administration of VPA is temporarily not feasible. At a median dose of 375 mg administered over 1 h infusion, VPA was safe and well tolerated in 318 patients hospitalized for seizures (Devinsky et al., 1995; Bialer et al., 2004). Naritoku and Mueed demonstrated the safety of an intravenous (loading) dose of VPA when a rapid increase in VPA serum level was required to stop recurrent seizures. A mean dose of 19.4 mg/kg infused at 20 and 50 mg/min was well tolerated in 20 patients with epilepsy (Naritoku & Mueed, 1999). Cloyd et al. studied the pharmacokinetics of VPA in 122 epileptic patients following an intravenous dosing of VPA (up to 15 mg/kg) given as an intravenous infusion at a rate of 1.5 or 3 mg/kg per minute (Cloyd et al., 2003). VPA peak plasma concentration was 94 mg/L and fell below 50 mg/L within 3 h in induced and 6 h in noninduced patients. VPA mean (standard deviation, SD) volume of distribution was 0.21 (0.044) L/kg and its fraction unbound to plasma albumin decreased from 15% at 94 mg/L to 9% at 45 mg/L. The authors concluded that VPA infusions of up to 3 mg/kg per minute produce predictable total VPA concentrations when induction status and albumin levels are considered. A study in 102 adults patients who received standardized high doses of Na-VPA in various emergency situations including SE, showed that 85.6% of the patients achieved the therapeutic goal of seizure-free status within <15 min and maintaining it for at least 12 h (Peters & Pohlmann-Eden, 2005). Although treatment of SE with VPA holds promise due to its safety profile and ease of administration, the experience with VPA in the treatment of SE has been limited to several small studies.

Carbamazepine (CBZ), a neutral water-insoluble compound, presents difficulties when formulating in a parenteral preparation. However, the water solubility of CBZ can be greatly enhanced by solubilizing it in (or forming a complex with) the cyclodextrin derivative, 2-hydroxypropyl-ß-cyclodextrin (Loscher et al., 1995). Studies in dogs indicated that intravenous administration of the CBZ–cyclodextrin complex was well tolerated. Clinical trials with a patent-protected parenteral formulation of CBZ are ongoing to characterize the pharmacokinetics of CBZ after intravenous administration and to provide a consistent transition therapy for patients on oral CBZ. Such intravenous formulations offer valuable, short-term treatment options for patients scheduled for surgery and for patients who cannot be treated with oral CBZ due to emergency situations, loss of consciousness, or gastrointestinal disturbances. Finally, such parenteral preparations could prove useful in acute, critical care situations such as SE.

An intravenous formulation of levetiracetam (LEV) has been developed and was recently approved by the U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMEA) after it was found to be bioequivalent to the commercially available oral formulation of LEV (Ramel et al., 2006a). The recommended dosage of 1,000–3,000 mg/day must be diluted in >100 ml compatible diluents (e.g., 0.9% NaCl, D5W) and administered as a 15-min infusion. This formulation has been approved in the European Union and by the FDA (Bialer et al., 2007, 2009). Intravenous LEV appears to be well tolerated in healthy adults even at fast infusion rates (1,500–2,500 mg administered over 5 min) and provides a useful alternative for patients unable to take LEV orally (Ramel et al., 2006b;Knake et al., 2008; Ruegg et al., 2008). Treatment experience with intravenous LEV of the first 50 critically ill patients showed efficacy, defined as cessation of seizure activity or prevention of its recurrence in 41 of 50 patients (82%) (Ruegg et al., 2008). The lack of drug interactions and hypnotic side effects coupled with minimal cardiac and peripheral venous effects make LEV a possible and more attractive alternative than benzodiazepines, PB or PHT (Knake et al., 2008; Ruegg et al., 2008).

The new water-soluble AED lacosamide has a water solubility of 20 mg/ml and a complete oral bioavailability. Consequently, it was developed in multiple bioequivalent formulations of oral tablets, aqueous intravenous preparation (10 mg/ml) for administration as 30- and 60-min infusions, and syrup (15 mg/ml). Lacosamide has a linear pharmacokinetics over a dose range of 100–800 mg/day and a half-life of 13 h. About 40% of the lacosamide dose is excreted unchanged in the urine and 30% as an inactive desmethyl metabolite (Beyrueter et al., 2007; Bialer et al., 2009). An intravenous formulation of lacosamide was developed to facilitate treatment of patients receiving lacosamide who temporarily become unable to take oral medications. Intravenous lacosamide is a stable aqueous solution that does not require dilution prior to administration and is intended to deliver 200 mg lacosamide over 30 or 60 min (Krauss et al., 2006; Biton et al., 2008). In phase I clinical trials it was well tolerated and the reported adverse events were mostly mild and similar to the ones described for oral lacosamide (Bialer et al., 2004). Bioequivalence has been demonstrated between oral and intravenous infusion (30 and 60 min) of lacosamide. The highest single dose was 300 mg (Kropeit et al., 2004; Bialer et al., 2007). Infusion over 15 min was nearly bioequivalent, with a slightly higher Cmax and equivalence for area under the concentration time curve (AUC) (Bialer et al., 2009). A recent study in 60 patients randomized showed that intravenous lacosamide, administered as 60- or 30-min infusion twice daily (200–600 mg/day) has a similar safety and tolerability profile to oral lacosamide when used as replacement therapy (Biton et al., 2008). In August 2008 the EMEA approved lacosamide (Vimpat, UCB, Brussels, Belgium) in convenient-to-administer formulations (oral tablets, intravenous, and syrup) for the adjunctive treatment of partial-onset seizures. Subsequently, the FDA approved lacosamide in October 2008. The availability of aqueous intravenous preparation of lacosamide will stimulate its use in SE.

In conclusion, parenteral formulations of AEDs are feasible for water-soluble AEDs. In order to be administered in an aqueous injection, water-insoluble AEDs need to be formulated in a chemical drug delivery or a prodrug (e.g., fosphenytoin) or via solubilization in a pharmaceutical drug delivery system (e.g., CBZ). Parenteral preparations contribute significantly to the antiepileptic armament and are essential in the treatment of patients who cannot be given AEDs orally. The global sales of fosphenytoin (only available parenterally) in 2006, 2007, and 2008 were $71, $55, and $12 million (the drop in sales is due to generic fosphenytoin products available since 2007), respectively, compared to $300, 338, and 258 million for oral phenytoin (IMS, 2009). Although the market for parenteral AEDs per se is small (as reflected by fosphenytoin), the fact that injectable formulations serve as an introduction for oral medication to which patients will be switched upon release from the hospital is an incentive for the pharmaceutical industry to develop parenteral formulations for additional AEDs, even if they are water-insoluble compounds.


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Disclosure: The author has received speakers or consultancy fees from BIAL, Bioline, Desitin, Gerson Lehrman Group Councils, Janssen-Cilag, Jazz Pharmaceuticals, Johnson & Johnson, Ovation, NeuroAdjuvants, Neurocrine Biosciences, Novonordisk, Rekah, Shire, Teva, and UCB Pharma. In the last 3 years, the author received research grants from Jazz Pharmaceuticals and the Epilepsy Therapy Development Project and has been involved in the design and development of new antiepileptics and CNS drugs.