The Clinical Pharmacokinetics of the New Antiepileptic Drugs

Abstract

Summary: Because pharmacokinetics is a major determinant of the magnitude and duration of pharmacologic response, understanding the kinetic properties of the new antiepileptic drugs (AEDs) is essential for the correct use of these compounds in clinical practice. After oral administration, absorption is rapid and relatively efficient for the new AEDs, the most notable exception being gabapentin, whose bioavailability decreases with increasing dosage. None of the new AEDs is extensively bound to plasma proteins except for tiagabine, which is over 95% protein-bound. The route of elimination differs to an important extent from one compound to another, and elimination half-lives range from over 30 h for zonisamide to 5-7 h for gabapentin. For all drugs that are metabolized, half-life is shortened and clearance is increased when patients receive concomitant enzyme-inducing agents such as barbiturates, phenytoin, and carbamazepine. Lamotrigine metabolism is markedly inhibited by valproic acid, and felbamate may increase the serum levels of most other AEDs. Felbamate, topiramate, and oxcarbazepine may also reduce the efficacy of the contraceptive pill by stimulating its metabolism. Key Words: AntiepilepticsPharmacokinetics-Drug interactions.To exert their therapeutic effects, antiepileptic drugs CLINICAL PHARMACOKINETICS (AEDs) must be absorbed and reach their sites of action in the brain at concentrations sufficient to produce the desired pharmacologic response. The pharmacokinetic profile is a major determinant of the magnitude and duration of drug action and is one of the factors to be considered in determining the optimal number of daily doses and the minimal interval that should elapse between dosage adjustments. For any given drug, pharmacokinetics may vary markedly from one patient to another (in relation to genetic background, age, physiologic states such as pregnancy, associated disease, and concomitant treatments), resulting in altered dosage requirements. Therefore, full understanding of the pharmacokinetic properties of individual compounds, and the factors affecting them, is essential for correct use of AEDs in clinical practice. Over the past decade, several new AEDs (felbamate, gabapentin, lamotrigine, oxcarbazepine, tiagabine, topiramate, vigabatrin, and zonisamide) have been introduced into routine clinical practice in a number of counThe pharmacokinetics of the new AEDs have been evaluated in healthy volunteers and in patients with epilepsy receiving a variety of concomitant treatments. For vigabatrin and for monohydroxycarbazepine (the active metabolite of oxcarbazepine), evaluation of pharmacokinetic properties is complicated by the presence of an asymmetric carbon in the molecule, which determines the existence of two different stereoisomers. Although vigabatrin is administered as a racemic mixture of the (R)-and (S)-isomers, only the (S)-form is pharmacologically active, and pharmacokinetic data for vigabatrin quoted in' this review refer to the (S)-enantiomer. In the case of monohydroxycarbazepine...

Population pharmacokinetics of lamotrigine in Chinese children with epilepsy

“…Including the quantitative TBW covariate, LTG CL in the final model proposed was 0.039 L·h -1 ·kg -1 , which is higher than the values of approximately 0.021 to 0.035 L·h -1 ·kg -1 that were reported in PK studies evaluating small numbers of adult patients and healthy adult volunteers using standard approaches (2-stage methods with a 1-compartment model) [8][9][10]24] . Our study has shown a nonlinear increase of the CL and V d of LTG with an increase in total body weight.…”

“…Despite LTG's wide clinical use, standard npg dosage regimens continue to be used even though they may often be suboptimal because of the high variability found in CL values in the target population [7,10,[13][14][15][16][17][18] . This observation, together with previous studies that have established definable relationships between LTG blood concentrations and therapeutic and toxic effects [19][20][21] , justify TDM as an indicator of drug exposure for the individualization of LTG doses [4][5] .…”

“…The traditional method for calculating individual PK parameters was to collect multiple (up to [7][8][9][10] blood samples from a single patient at different times after a single dose. This method was not always accepted by patients, especially children.…”

“…A one-compartment, open kinetic model with first-order absorption and elimination (specified to NONMEM by the ADVAN2 and TRANS2 routines) was assumed according to the available bibliographic information [7][8][9][10] . Because the LTG steady-state trough plasma concentration data collected did not provide information about the extent and rate of absorption processes, the bioavailability (F) and absorption rate (K a ) were fixed at 1.0 and 1.0 h -1 , respectively [7] .…”

New Add-on Therapy for Partial-onset Epilepsy

“…However, medications that induce hepatic enzymes may decrease lamotrigine's half-life to 14-16 hours, and dosing must be adjusted accordingly. 10,15 Oral contraceptives decrease lamotrigine half-life, but as combined oral contraceptive monthly packs have seven days with no hormonal placebo pills, lamotrigine levels can rise by as much as 40%, leading to monthly flucutuations and causing side effects.…”