Thomas R. Browne

Efficacy and Tolerability of the New Antiepileptic Drugs, II: Treatment of Refractory Epilepsy. Report of the TTA and QSS Subcommittees of the American Academy of Neurology and the American Epilepsy Society

Summary:  Purpose: To assess the evidence demonstrating efficacy, tolerability, and safety of seven new antiepileptic drugs [AEDs; gabapentin (GBP), lamotrigine (LTG), topiramate (TPM), tiagabine (TGB), oxcarbazepine (OXC), levetiracetam (LEV), and zonisamide (ZNS), reviewed in the order in which these agents received approval by the U.S. Food and Drug Administration] in the treatment of children and adults with newly diagnosed partial and generalized epilepsies.

Randomized, Controlled Clinical Trial of Zonisamide as Adjunctive Treatment for Refractory Partial Seizures

Summary:  Purpose: This study was designed to evaluate efficacy and safety of zonisamide (ZNS) as adjunctive treatment for patients with refractory partial seizures.

Pharmacology and pharmacokinetics of fosphenytoin

Fosphenytoin sodium, a phosphate ester prodrug of phenytoin, was developed as a replacement for parenteral phenytoin sodium.Unlike phenytoin, fosphenytoin is freely soluble in aqueous solutions, including standard IV solutions, and is rapidly absorbed by the IM route. Fosphenytoin is metabolized (conversion half-life of 8 to 15 min) to phenytoin by endogenous phosphatases. Therapeutic free (unbound) and total plasma phenytoin concentrations are consistently attained after IM or IV administration of fosphenytoin loading doses. Fosphenytoin has fewer local adverse effects (e.g., pain, burning, and itching at the injection site) after IM or IV administration than parenteral phenytoin. Systemic effects related to the CNS are similar for both preparations, but transient paresthesias are more common with fosphenytoin. NEUROLOGY 1996;46(Suppl 1): S3-S7

Stable Isotope Techniques in Early Drug Development: An Economic Evaluation

Stable isotope labeled (SIL) drug methods are compared with standard methods for performing early (phases I and IIa) drug development studies (mass balance, bioavailability, single‐dose volunteer and patient, multiple‐dose volunteer and patient). SIL methods offer considerable reduction in the cost (>50%) and number of subjects (67%) required for bioavailability and multiple‐dose patient studies. Moreover, a complete early drug development program is described for optimally combining SIL and standard studies, which can reduce cost by 23% and number of subjects by 36% compared with a program using standard methods. These reductions should result in development time savings of at least one year.

Levetiracetam, a new antiepileptic agent: lack of in vitro and in vivo pharmacokinetic interaction with valproic acid.

Summary:  Purpose: The novel antiepileptic drug (AED) levetiracetam (LEV; Keppra) has a wide therapeutic index and pharmacokinetic characteristics predicting limited drug‐interaction potential. It is indicated as an add‐on treatment in patients with epilepsy, and thus coadministration with valproic acid (VPA) is likely. These studies were performed to determine whether coadministration of LEV with VPA might result in pharmacokinetic interactions.

Pharmacokinetics of antiepileptic drugs

Enzymatic biotransformation is the principal determinant of the pharmacokinetic properties of most antiepileptic drugs (AEDs), although some agents are excreted by the kidneys predominantly as unchanged drug. Most AEDs exhibit linear enzyme kinetics, in which changes in daily dose lead to proportional changes in serum concentration if clearance remains constant. There are several important applications of pharmacokinetics in clinical practice. Established therapeutic ranges help guide drug administration to achieve serum concentrations that control seizures without causing intolerable toxicity. Determination of the elimination half-life may provide a basis for selecting a dosing interval and predicting the time to steady-state concentration. However, the traditional concept of administering a drug at intervals equal to one elimination half-life does not apply to some drugs. With vigabatrin, the half-life of biologic activity greatly exceeds the half-life of elimination. In situations in which it is desirable to achieve a steady-state serum concentrations immediately, a loading dose can be calculated from a drugs volume of distribution and its desired serum concentration. Many AEDs have the potential to be involved in pharmacokinetic drug interactions when they are co-administered with other AEDs or other medications. These interactions usually involve changes in the rate of biotransformation or in the protein binding of one or both co-administered drugs.

Kinetic equivalence of stable-isotope-labeled and unlabeled phenytoin

Stable isotope labeling (SIL) of a drug results in a higher molecular weight than that of the unlabeled drug. SIL tracer doses can be quantitated separately from unlabeled drug by gas chromatography–mass spectrometry (GC‐MS) without exposing the patient to radiation. The higher molecular weight of SIL drug could cause a higher energy of activation for (and slowing of) metabolic reactions (“isotope effect”). To evaluate possible isotope effect, three dogs and three men were infused with a mixture containing equal amounts of SIL (2‐13C‐1,3‐15N2) and unlabeled phenytoin (PHT). Plasma and urine were collected at regular intervals. Concentrations of SIL and unlabeled PHT and HPPH (the major metabolite of PHT) were determined by GC‐MS. Within each subject there was no trend for concentrations of SIL PHT or HPPH to be higher or lower than concentrations of their unlabeled analogs (p > 0.20 to 0.90). There was no difference in the distribution and elimination half‐lifes (t½s), volume of distribution, volume of central compartment, or clearance of the two forms of PHT. Thus, no isotope effect was found.

Bioavailability of ACC-9653 (Phenytoin Prodrug)

Summary: The bioavailability of phenytoin from ACC‐9653 versus intravenously administered sodium phenytoin was determined using a crossover design for intravenous and intramuscular administration of ACC‐9653 to healthy volunteers. Absolute bioavailability of phenytoin derived from ACC‐9653 in each subject was calculated as the ratio of the phenytoin area under the plasma concentration time curve for time 0 to infinity [AUC(0‐inf)] after ACC‐9653 divided by the phenytoin AUC(O‐inf) after intravenous sodium phenytoin. The mean absolute bioavailability of ACC‐9653 was 0.992 after intravenous administration and 1.012 after intramuscular administration. These data establish that the bioavailability of ACC‐9653 is complete following intravenous or intramuscular administration in single‐dose volunteer studies. The absolute bioavailability of phenytoin derived from ACC‐9653 in subjects with therapeutic plasma phenytoin concentrations is being studied in patients given simultaneous infusions of stable isotope‐labeled tracer doses of ACC‐0653 and sodium phenytoin.

Studies with stable isotopes II: Phenobarbital pharmacokinetics during monotherapy.

Six healthy adults receiving no other medications were given tracer doses of 90 mg of stable isotope‐labeled phenobarbital (PB) intravenously before, and four weeks after, and 12 weeks after beginning therapy. Serum samples were collected for 96 hours after each injection, and the concentration of stable isotope‐labeled PB in each sample was determined by gas chromatographic mass spectrometry. The volume of distribution, elimination half‐life, and total clearance of PB did not differ significantly on any of the three occasions measured. Phenobarbital clearance did not correlate significantly with total PB serum concentration. Clearances determined from single‐dose studies before beginning PB therapy accurately predicted steady‐state PB serum concentrations. Therefore, it is not necessary to adjust PB dosage for time‐dependent or dose‐dependent changes in clearance during monotherapy. In addition, clearance or serum concentration determined at one dosing rate directly predicts serum concentration at another dosing rate.

Methsuxirnide for complex partial seizures Efficacy, toxicity, clinical pharmacology, and drug interactions

Methsuximide (MSM; Celontin) was administered for 8 weeks to 26 patients with complex partial seizures (CPS) refractory to phenytoin and carbamazepine and phenobarbital or primidone. A 50% or greater reduction in CPS frequency was obtained in eight patients. MSM therapy was continued chronically in these eight patients, and five continued to have a 50% or greater reduction in CPS frequency after 3 to 34 months of follow-up. Drowsiness, gastrointestinal disturbance, hiccups, irritability, and headache were the common side effects of MSM. No serious toxicity occurred. N-desmethylmethsuximide was the principal substance detected in plasma and had the following pharmacokinetic values: accumulation half-life, 49.7 hours; time to steady state, 10.4 days; elimination half-life, 72.2 hours; therapeutic range of plasma concentration, 10 to 30 mg per liter. Plasma concentrations of phenytoin and phenobarbital derived from primidone rose significantly (p < 0.05) after addition of MSM.