Effect of levetiracetam on the pharmacokinetics of adjunctive antiepileptic drugs: A pooled analysis of data from randomized clinical trials
ABSTRACT The purpose of this study was to determine the influence of levetiracetam on the steady-state serum concentrations of other commonly used antiepileptic drugs (AEDs). Serum AED concentrations were measured at baseline and after adjunctive therapy with levetiracetam (1000-4000 mg/day) or placebo in four phase III trials in patients with refractory partial epilepsy receiving stable AED dosages. The data were pooled, and repeated measures covariance analysis was used to calculate the ratio (and 90% confidence intervals) of the geometric mean serum drug concentrations during adjunctive levetiracetam therapy relative to baseline. Levetiracetam did not increase or decrease mean steady-state serum concentrations of carbamazepine, phenytoin, valproic acid, lamotrigine, gabapentin, phenobarbital, or primidone. For each of these AEDs, the 90% confidence interval of the geometric mean drug concentrations ratio was included within the 80-125% bioequivalence range. Serum concentrations of these AEDs did not change over time after adjunctive levetiracetam therapy, irrespective of the dosage of levetiracetam used. For vigabatrin, there was no evidence for a significant change in serum drug concentration after the addition of levetiracetam, but the number of observations was too small for the limits of the confidence interval to fall within the 80-125% range. Thus, adjunctive therapy with levetiracetam does not influence the steady-state serum concentrations of concomitantly administered carbamazepine, phenytoin, valproic acid, lamotrigine, gabapentin, phenobarbital, or primidone. Consequently, no need for adjusting the dosages of these AEDs is anticipated when levetiracetam is added on or removed from a patient's therapeutic regimen.
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ABSTRACT: The intravenous (iv) formulation of levetiracetam has been available in clinical practice worldwide for several years, but not in Japan. Two open-label studies were conducted: Study A evaluated the bioequivalence of iv and oral tablet formulations in healthy Japanese volunteers; and Study B subsequently compared the pharmacokinetics of iv levetiracetam in healthy Japanese and Caucasian volunteers. Study A had a randomised, two-way crossover design; a single 1,500 mg levetiracetam dose was administered as a 15-min iv infusion and as 3 × 500 mg oral tablets to Japanese volunteers. In Study B, 1,500 mg levetiracetam was administered as single and repeated 15-min iv infusions to Japanese and Caucasian volunteers. Overall, 26/27 volunteers completed Study A and 32/32 (16 Japanese; 16 Caucasian) completed Study B. In Study A, the point estimate and 90 % confidence interval (CI) for the geometric least squares mean (LSM) ratio (iv vs oral) were fully included within the acceptance range for bioequivalence (0.85-1.25) for the area under plasma concentration-time curve from 0 to last quantifiable observation (AUClast 0.97 [0.95, 0.99]), but not for the maximum plasma concentration (C max 1.64 [1.47, 1.83]). In Study B, after a single iv infusion, the point estimates (90 % CI) for the geometric LSM ratio (Japanese vs Caucasian) for body weight-normalised C max and AUClast were 1.21 (1.07, 1.36) and 0.97 (0.90, 1.04), respectively. Corresponding values after repeated iv infusions were C max,ss 1.01 (0.91, 1.12) and AUCτ,ss 0.89 (0.83, 0.96). Levetiracetam was well tolerated in both studies. Study A did not demonstrate the bioequivalence of single doses of levetiracetam 1,500 mg administered as an iv infusion and as oral tablets in healthy Japanese adults. Study B, however, showed that pharmacokinetic profiles were generally similar between Japanese and Caucasian adults after single and repeated iv infusions of levetiracetam 1,500 mg.European Journal of Drug Metabolism and Pharmacokinetics 10/2014; DOI:10.1007/s13318-014-0227-4 · 1.31 Impact Factor
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ABSTRACT: Background and Objective The anti-epileptic drug levetiracetam is excreted renally. The objective of this trial was to evaluate the pharmacokinetics of levetiracetam in Japanese patients with renal impairment including end-stage renal disease (ESRD) to confirm that existing dosing instructions-based on data from European patients-are appropriate in a Japanese population. Methods This was a nonrandomised, open-label trial. Six participants were allocated to each of five groups (normal renal function, mild, moderate and severe renal impairment and ESRD); 30 participants in total. Participants received a single dose of levetiracetam 500 mg (normal or mild), 250 mg (moderate or severe), or 500 mg followed by 250 mg post-haemodialysis (ESRD). Blood and urine samples were obtained serially for levetiracetam and metabolite determinations. Noncompartmental pharmacokinetic parameters were calculated and steady-state profiles were simulated using the superposition method. Results In this trial, levetiracetam total clearance decreased proportionally with creatinine clearance: 52, 31, 25, 20 and 11 mL/min/1.73 m(2) in healthy controls and in patients with mild, moderate, severe renal impairment, and ESRD, respectively. Simulated levetiracetam plasma profiles using the recommended dose adjustments were within the range for normal renal function. Overall, results from this trial were consistent with historical European data. Conclusion These findings confirm that the dosing instructions are appropriate for Japanese patients with renal impairment including ESRD.Clinical Drug Investigation 10/2014; 34(11). DOI:10.1007/s40261-014-0237-7 · 1.70 Impact Factor
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ABSTRACT: Hearing loss has been reported with valproic acid (VPA) use. However, this is the first case of VPA-induced hearing loss that was tested and confirmed with a VPA rechallenge, supported by serial audiometry and pharmacokinetic modelling. A 39-year-old truck driver with temporal lobe epilepsy was treated with VPA at 400 mg, twice daily, and developed hearing loss after each dose, but recovered within three hours. Hearing loss fully resolved after VPA discontinuation. Audiometry performed five hours after VPA rechallenge showed significant improvement in hearing thresholds. Pharmacokinetic modelling during the VPA rechallenge showed that hearing loss occurred at a level below the therapeutic range. Brainstem auditory evoked potential at three months after VPA discontinuation showed bilateral conduction defect between the cochlear and superior olivary nucleus, supporting a pre-existing auditory deficit. VPA may cause temporary hearing threshold shift. Pre-existing auditory defect may be a risk factor for VPA-induced hearing loss. Caution should be taken while prescribing VPA to patients with pre-existing auditory deficit.Epileptic disorders: international epilepsy journal with videotape 08/2014; 16(3). DOI:10.1684/epd.2014.0671 · 0.90 Impact Factor