Clinical pharmacology of parenteral use of antiepileptic drugs

Intravenous (i.v.) administration of antiepileptic drugs (AEDs) produces the most rapid onset of action, as it is delivered directly into the bloodstream and immediately produces maximal plasma concentration (C0= Cmax). In addition to its therapeutic value, i.v. administration is essential in investigating the pharmacokinetics (PK) or clinical pharmacology of drugs, as it bypasses absorption and focuses on the disposition (distribution plus elimination) of drugs. Consequently due to its direct delivery of drugs to the blood, i.v. injection or infusion is the reference route for absolute bioavailability calculations. Other parenteral routes like intramuscular (im) or subcutaneous (sc) administration are examples of extravascular (ev) administration involving absorption processes and therefore, drug plasma profiles produced are similar to the one obtained following oral administration of conventional (immediate release) formulations. Most AEDs exhibit linear (concentration-independent) PK and therefore their major PK parameters: clearance (CL), apparent volume of distribution (V), and half-life (t1/2) are not affected by the route of administration or by the rate or extent of absorption (Bialer and Cloyd, 1995). Changes in route of administration or in the parenteral (ev) formulation only affect the extent and rate of absorption, whereas the disposition is an intrinsic property of the AED or the active entity. Similar to oral formulations, parenteral preparations intended for im or sc injections may be formulated to have a rapid or slow rate of absorption. The preferred parenteral preparations are aqueous solutions that generally distribute rapidly from the administration site. Hydroalcoholic, oily, or suspension vehicles may result in slow and sustained absorption, side effect of the nonaqueous solvents (e.g., propylene glycol) and unlike aqueous injections cannot be diluted for infusions. The differences between aqueous and hydroalcoholic parenteral preparations of AEDs are best illustrated in the development of fosphenytoin. Fosphenytoin is a disodium phosphate ester of 3-hyroxymethyl of phenytoin developed as a replacement for standard injectable phenytoin sodium. The water solubility of fosphenytoin is 75,000 mg/L versus only 20 mg/L for phenytoin sodium. Consequently, fosphenytoin was designed and developed as an aqueous injectable phenytoin prodrug to avoid the local complications associated with parenteral phenytoin such as i.v. fluid incompatibilities, patient discomfort, vein irritation/tissue damage, and muscle necrosis after im administration. The parenteral preparation of phenytoin sodium is a hydroalcoholic mixture of 40% propylene glycol, 10% alcohol, and 50% water with the pH adjusted to 12, necessary to provide 50 mg/ml solution of sodium phenytoin, while fospehnytoin is an aqueous solution. Fosphenytoin is administered either by i.v. or im 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 fosphenytoin solutions diluted to phenytoin concentrations of 1, 8, and 20 mg/ml in 0.9% NaCl, D5W, and other 11 i.v. fluids were physically compatible and chemically stable. Clinical studies in adults and children indicate that im and i.v. of fosphenytoin were well tolerated, safe and rapidly and completely converted to phenytoin (Bialer et al., 2002). Sodium valproate injection (Depacon) was approved in the United States in 1996 for intravenous use in epileptic patients for whom oral administration of VPA is temporarily not feasible. At a median dose of 375 mg administered over 1 h infusion, sodium valproate 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 i.v. (loading) dose of sodium valproate 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 and Mueed, 1999). Cloyd et al. studied the pharmacokinetics of VPA in 122 epileptic patients following an i.v. dosing of sodium valproate (up to 15 mg/kg) given as an i.v. infusion at a rate of 1.5 or 3 mg/kg/min (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 (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/min produce predictable total VPA concentrations when induction status and albumin levels are considered. Ramsay et al. evaluated the safety of sodium valproate infusion utilizing as a primary safety endpoint the changes in the 5-min and minimum post first infusion blood pressure. They concluded that i.v. dosages up to 15 mg/kg given at rates of 1.5 and 3.0 mg/kg/min were well tolerated in this patient population (Ramsay et al., 2003). Recently, Limdi et al. demonstrated that rapid administration of undiluted Depacon was safe and well tolerated infusion rate up to 10 mg/kg/min and doses up to 30 mg/kg (Limdi et al., 2007). Carbamazepine (CBZ), a neutral water-insoluble compound, presents difficulties when formulating it in a parenteral preparation. However, the water solubility of CBZ can be greatly enhanced by solubilizing it in (or forming a complex with) the cylcodextrin derivative, 2-hydroxypropyl-ß-cyclodextrin (Loscher et al., 1995). Studies in dogs indicated that i.v. administration of the CBZ cyclodextrin complex was well tolerated. Ovation Pharmaceuticals is currently conducting clinical trials with a patent-protected i.v. formulation of CBZ (i.v. CBZ) to characterize the pharmacokinetics of CBZ after i.v. administration and to provide a consistent transition therapy for patients on oral CBZ (Collins, 2007). The primary objectives of these studies are: (a) to assess the safety and tolerability of i.v. CBZ given as an i.v. infusion over 15 and 30 min; (b) to compare the pharmacokinetics of CBZ following repetitive i.v. dosing (7 days) at steady-state to that obtained after a single oral dose. The secondary objectives are to assess the pharmacokinetics, safety, and tolerability of i.v. CBZ following rapid i.v. infusion (2 and 5 min) and in patients with mild or moderate impairments (Collins, 2007). CBZ i.v. 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 GI disturbances. Finally, such parenteral preparations could prove useful in acute, critical care situations such as status epilepticus (SE). The goals of pharmacological therapy of 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. New AEDs have provided alternatives to the traditional treatment paradigms for SE. However, most new AEDs are still not available in a parenteral formulation and thus cannot be utilized in the treatment of SE. The first line drugs are the benzodiazepines: lorazepam and diazepam that are used for the initial treatment of SE. Diazepam achieves high brain concentrations and has a slightly faster onset of action. However, diazepam redistributes rapidly to peripheral fats and consequently its clinical effectiveness is limited to 20–30 min. Therefore, diazepam treatment of SE needs to be followed with a second drug such as lorazepam. Lorazepam has a more favorable pharmacokinetic profile than diazepam and its duration of action exceeds 12 h. Phenytoin or its parenteral prodrug fosphenytoin are also utilized in the treatment of SE with a loading dose of 1 g or 20 mg/kg administered at a maximal rate of 50 mg/min. In the absence of 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 i.v. dosing are cardiovascular including hypotension and QT prolongation. Phenobarbital 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. Phenobarbital's long half-life and the presence of an active metabolite are drawbacks in terms of adverse effects. Although treatment of SE with VPA holds promise, the experience with VPA in the treatment of SE has been limited to several small studies. VPA's main advantage over other AEDs appears to be its safety profile and ease of administration. An i.v. formulation of levetiracetam has been developed and was found to be bioequivalent to the commercially available oral formulation of levetiracetam (Ramel, 2006a). The recommended dose 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). Intravenous levetiracetam 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 levetiracetam orally (Baulac, 2005; Ramel, 2006b). A recent study in dogs showed that following im administration, levetiracetam is rapidly and completely absorbed and suggested that levetiracetam should be evaluated for im administration to humans (Goel et al., 2006). A recent multicenter, open-label study evaluated the short-term tolerability of a 15-min i.v. infusions of levetiracetam (500–1,500 mg/100 ml, bid) and found that it was well tolerated and provides a practical alternative in patients with partial onset seizures that temporarily are unable to take levetiracetam orally (Baulac et al., 2007). Recently, an i.v. formulation of the water-soluble new AED lacosamide was developed to facilitate treatment of patients receiving lacoamside who temporarily become unable to take oral medications. Intravenous lacosamide is a stable aqueous solution of the parent compound (10 mg/ml) 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). In phase I, clinical trials lacosamide was well tolerated and the reported adverse events were mostly mild and similar to the ones described for oral lacoasmide (Bialer et al., 2004). Bioequivalence has been demonstrated between oral and i.v. infusion (30 and 60 min) of lacosamide. The highest single dose was 300 mg. After i.v. dosing, lacosamide plasma concentration-time curves were similar to those obtained after oral administration and the metabolic profile was comparable to oral dosing (Bialer et al., 2007). A preliminary report describes the pharmacokinetics of lamotrigine (LTG) following an intravenous administration of stable-labeled LTG formulation (Remmel et al., 2006). Epileptic patients on steady-state maintenance LTG therapy were given a single 50 mg replacement of the (13C2, 15N]-LTG formulation as part of their daily LTG regimen. Five younger women (age 25–48 years) have completed the study. LTG doses ranged from 200 to 800 mg/day. These preliminarily data indicate that the investigated LTG i.v. formulation is safe and well tolerated when administered to relatively healthy adult patients (Remmel et al., 2006). In conclusion, parenteral formulations of AEDs are quite feasible for AEDs that are water-soluble. 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 (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 (that is only available parenterally) in 2004 and 2005 were only $63 and $70 millions, respectively, compared to $326 million of oral phenytoin (IMS, 2006). 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, shall serve as an incentive for the pharmaceutical industry to develop parenteral formulations for additional AEDs even if they are water-insoluble compounds.