Minimal to no transfer of certolizumab pegol into breast milk: results from CRADLE, a prospective, postmarketing, multicentre, pharmacokinetic study.

BACKGROUND: Women with chronic inflammatory diseases face uncertainty regarding the safety of biologics during breast feeding. CRADLE was the first industry-sponsored study to evaluate certolizumab pegol (CZP) concentrations in human breast milk and estimate average daily infant dose (ADID) of maternal CZP. METHODS: CRADLE (NCT02154425) was a pharmacokinetic study of lactating mothers receiving CZP. After ≥3 CZP doses, breast milk samples were collected across one dosing period (14 days for 200 mg every 2 weeks [Q2W]; 28 days for 400 mg every 4 weeks [Q4W]). Optimal analytical methods were developed to determine CZP and polyethylene glycol (PEG) levels in breast milk. ADID and relative infant dose (RID) were estimated. Safety events in mothers and infants were assessed. RESULTS: 19 CZP-treated mothers were screened; 17 entered the sampling period: 16 on 200 mg Q2W, 1 on 400 mg Q4W. 77/137 (56%) breast milk samples had no measurable CZP. For 4/17 mothers, all samples were below the lower limit of quantification (LLOQ). Estimated ADID was 0-0.0104 mg/kg/day; median RID: 0.15%. PEG was undetectable in 134/137 samples (results could not be determined in three samples). Infants of CZP-exposed mothers had a safety profile consistent with that of unexposed similar-age infants. CONCLUSION: When quantifiable, CZP concentrations were <3× LLOQ (<1% plasma concentration observed with therapeutic dose), indicating no/minimal CZP transfer from plasma to breast milk. RID was 0.15% of maternal dose; <10% is considered unlikely to be of clinical concern. No PEG transfer was observed. CZP absorption by infants via breast milk is unlikely due to its low oral bioavailability and Fc--free molecular structure. These findings are reassuring and support continuation of CZP treatment during breast feeding. TRIAL REGISTRATION NUMBER: NCT02154425; Results.

Pharmacokinetics, Safety and Bioequivalence of Levetiracetam Intravenous Infusion and Oral Tablets in Healthy Chinese Subjects.

BACKGROUND AND OBJECTIVE: Levetiracetam is available in China as adjunctive oral therapy for partial-onset seizures. This study was conducted to evaluate the bioequivalence between single-dose intravenous infusion and oral levetiracetam 1500 mg (Part A), and to assess the pharmacokinetics of multiple-dose intravenous infusion at the same dose (Part B) in healthy Chinese subjects. METHODS: Part A was an open-label, crossover comparison (intravenous vs. oral), while Part B was a double-blind, parallel-group study of intravenous levetiracetam versus intravenous placebo administered for 5 days. RESULTS: Bioequivalence was demonstrated between the 45-min intravenous infusion and oral tablets, with geometric mean area under the plasma concentration-time curve (AUC) from time 0 to infinity (AUC(∞)) 492.3 and 506.8 µg·h/mL, and geometric mean maximum concentration (Cmax) 65.12 and 55.93 µg/mL for intravenous infusion and oral dosing, respectively. Linear pharmacokinetics were demonstrated (geometric least-squares mean AUC during the dosing interval τ at steady state (AUC(τ,ss)) 475.6 µg·h/mL; geometric least-squares mean AUC(∞) after single dose 501.7 µg·h/mL; linearity factor = 0.948). Geometric mean Cmax (77.44 µg/mL) and AUC(τ,ss) (475.6 µg·h/mL) of intravenous infusion levetiracetam 1500 mg after multiple doses were within the expected range, based on their respective single-dose values and the terminal half-life of levetiracetam after a single dose (7.13 h). A theoretical accumulation of approximately 40% would be expected after multiple doses, which is consistent with the calculated accumulation of 18.0 and 43.5% (Rmax and R(AUC), respectively). CONCLUSIONS: Intravenous infusion of levetiracetam is bioequivalent to oral levetiracetam in healthy Chinese subjects and is a suitable alternative for levetiracetam administration in patients who are temporarily unable to take their medication orally.

Pharmacokinetics of the antiepileptic drug levetiracetam in healthy Japanese and Caucasian volunteers following intravenous administration.

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.

Levetiracetam pharmacokinetics in Japanese subjects with renal impairment.

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.

Development of an integrated population pharmacokinetic model for oral levetiracetam in populations of various ages and ethnicities.

  Levetiracetam [E Keppra(®)] is a second generation antiepileptic drug for different types of epilepsy in adults and children ≥1 month. The objective is to develop a population pharmacokinetic model to describe the pharmacokinetics of levetiracetam in Japanese children and adults as well as North American children, the purpose being to explore potential dosing recommendations in Japanese children. Levetiracetam plasma concentration-time data were obtained from Japanese adult and pediatric clinical studies. The data were analyzed through non-linear mixed effects modelling. The model was used to perform simulations and compare the exposure in Japanese children and adults. It was subsequently extended to North American children through an external validation. A one-compartment model with first-order absorption and first-order elimination adequately described the data. The exposure parameters determined based on the simulations in children were well within the adult range. The external validation against historical data from North American children was successful. The integrated population pharmacokinetic model provided a good description of the data, confirming the similarity of levetiracetam pharmacokinetics in these various populations. In Japanese children, a target dose of 10 to 30 mg/kg twice daily ensures the same exposure as the recommended dose in Japanese adults of 500 to 1,500 mg twice daily.

Prospective Open-Label, Single-Arm, Multicenter, Safety, Tolerability, and Pharmacokinetic Studies of Intravenous Levetiracetam in Children With Epilepsy.

Levetiracetam given via intravenous administration has been shown to be an effective alternative in adults with epilepsy when oral administration is not feasible. This study was a prospective single-arm, multicenter study to assess tolerability, safety, and pharmacokinetics of intravenous levetiracetam in children with epilepsy. Children with epilepsy ages 1 month to 16 years requiring intravenous levetiracetam were enrolled. Assessments included vital signs, electrocardiogram, hematology, chemistry, plasma concentrations of antiepileptic medications, weight, physical/neurological examinations, and pharmacokinetics. A total of 52 patients were enrolled. Mild to moderate treatment-emergent adverse events occurred in 63%, the most frequent being pyrexia and dry mouth. Most other treatment-emergent adverse events were considered unrelated to intravenous levetiracetam administration. Therefore, intravenous levetiracetam in the acute setting was overall well tolerated in children 1 month to 16 years.

Retrospective population pharmacokinetic analysis of levetiracetam in children and adolescents with epilepsy: dosing recommendations.

OBJECTIVE: To characterize levetiracetam pharmacokinetics, identify significant covariate relationships and identify doses in children that achieve blood concentrations similar to those observed in adults. METHODS: Nonlinear mixed-effects modelling was used to analyse pooled data collected from 228 children with epilepsy aged 3 months to 18 years in five trials of adjunctive levetiracetam therapy. Simulations were used to identify dosing regimens achieving levetiracetam steady-state peak and trough plasma concentrations similar to those attained in adults receiving the recommended starting dose for adjunctive therapy (500 mg twice daily). The covariates considered for inclusion in the base model were age, bodyweight, gender, race, body surface area (BSA), body mass index (BMI), creatinine clearance (CL(CR)), levetiracetam dose, concomitant antiepileptic drug (AED) by category (neutral, enzyme inducer, inhibitor, combination of inducer and inhibitor), and benzodiazepines. RESULTS: A one-compartment model with first-order absorption and elimination best characterized the data. The following significant covariates were identified: (i) age on the absorption rate constant (k(a)); (ii) bodyweight, dose, CL(CR) and concomitant enzyme-inducing AED on plasma oral clearance (CL/F); and (iii) bodyweight on the apparent volume of distribution after oral administration (V(d)/F). The main explanatory covariates were age on k(a), bodyweight on CL/F and V(d)/F, and enzyme-inducing AED on CL/F, of which bodyweight was the most influential covariate. Dosing can be carried out with either 10 mg/kg of oral solution twice daily in children weighing <50 kg and a 500-mg tablet twice daily in those weighing >50 kg or, when patients favour a solid formulation, 10 mg/kg of oral solution twice daily in children weighing <20 kg, a 250-mg tablet twice daily in those weighing 20-40 kg, and a 500-mg tablet twice daily in those weighing >40 kg. All of these doses achieved steady-state peak and trough plasma concentrations similar to those observed in adults following the recommended starting dose for adjunctive therapy (500 mg twice daily). CONCLUSIONS: The most influential covariate of levetiracetam pharmacokinetics in children is bodyweight. A starting dose of levetiracetam 10 mg/kg twice daily ensures the same exposure in children as does 500 mg twice daily in adults.

Seletracetam (UCB 44212).

Better pharmacotherapies for epilepsy are needed for patients who are refractory to or have tolerability difficulties with current treatments. Seletracetam, a new drug in epilepsy development, is a pyrrolidone derivative structurally related to levetiracetam (trade name Keppra). It was discovered because of its high binding affinity to the synaptic vesicle 2A (SV2A) protein, which is now known to be the binding site for this family of compounds. Seletracetam shows very potent seizure suppression in models of acquired or genetic epilepsy, as well as high CNS tolerability in various animal models. Pharmacokinetic studies in animals suggest that seletracetam is rapidly and highly absorbed, with linear and time-independent pharmacokinetics. Seletracetam appears neither to inhibit nor to induce the major human drug metabolizing enzymes, and it demonstrates low plasma protein binding (<10%), which suggests a low potential for drug-drug interactions. Initial studies in humans demonstrated first-order monocompartmental kinetics with a half-life of 8 h and an oral bioavailability of >90%. Studies in healthy volunteers showed that the treatment emergent adverse events were of mild to moderate severity, were mostly of CNS origin and were resolved within 24 h. Altogether, these results suggest that seletracetam represents a promising new antiepileptic drug candidate, one that demonstrates a potent, broad spectrum of seizure protection and a high CNS tolerability in animal models, with initial clinical findings suggestive of straightforward pharmacokinetics and good tolerability.

Levetiracetam intravenous infusion: a randomized, placebo-controlled safety and pharmacokinetic study.

PURPOSE: The primary objective of this placebo-controlled study was to evaluate the safety and tolerability of levetiracetam (LEV) administered intravenously (IV) at higher doses and/or at a faster infusion rate than proposed. The secondary objective was to assess LEV pharmacokinetics. METHODS: Single ascending doses of LEV administered by IV infusion (2,000, 3,000, 4,000 mg over 15 min; 1,500, 2,000, 2,500 mg over 5 min) were evaluated in 48 healthy subjects in a randomized, single-blind, placebo-controlled study. RESULTS: All randomized subjects completed the study. Adverse events reported after IV administration of LEV (

Single-dose bioavailability of levetiracetam intravenous infusion relative to oral tablets and multiple-dose pharmacokinetics and tolerability of levetiracetam intravenous infusion compared with placebo in healthy subjects.

BACKGROUND: Antiepileptic drugs are usually administere dorally, but alternative routes of drug delivery may be required when oral administration is not feasible. OBJECTIVE: The purpose of this study was to evaluate the single-dose bioavailability of an IV formulation of levetiracetam relative to oral tablets and the multiple-dose tolerability and pharmacokinetics of this formulation compared with placebo in healthy subjects. METHODS: This study consisted of 2 phases. Subjects entered the first phase, which was a single-dose, randomized, open-label, 2-way crossover bioavailability comparison of a 15-minute IV infusion of levetiracetam 1,500 mg and three 500-mg oral tablets. Subjects then entered the second phase, a multiple-dose, randomized, double-blind, placebo-controlled (2:1), parallel-group tolerability and pharmacokinetic study, in which they received 9 successive doses of levetiracetam 1,500 mg IV or placebo at 12-hour intervals. Plasma levetiracetam concentrations were determined by gas chromatography with nitrogen-phosphorus detection. The comparison of bioavailability was based on the 90% CIs around the geometric mean ratios for AUC and C(max) (IV/oral). RESULTS: Eighteen subjects (9 men, 9 women) participated in the study. All subjects were white. Their mean (SD) age was 35.0 (9.3) years, mean weight 73.3 (14.2) kg, and mean body mass index 23.9 (2.5) kg/m(2). After a single dose, the IV infusion and oral tablet were similar in terms of C(max) (50.5 and 47.7 microg/mL, respectively) and AUC (392.4 and 427.9 pg x h/mL). The geometric mean IV/oral ratios were 92.2 (90 % CI, 89.0-95.6) for AUC and 103.7 (90% CI, 91.6-117.4) for C(max) indicating that the IV and oral formulations were bioequivalent. After multiple twice-daily infusions, steady state was reached within 48 hours. Seventeen (94%) of 18 subjects had >or=1 treatment-emergent adverse event after single-dose administration. During the single-dose phase, the incidence of treatment-emergent adverse events was 89% (16/18) for the IV formulation and 72% (13/18) for the oral tablets; during the multiple-dose phase, the incidence of treatment-emergent adverse events was 67% (8/12) in the IV levetiracetam group and 33% (2/6) in the placebo group. The most common adverse events in the single-dose phase were somnolence (61% IV vs 28% oral) and postural dizziness (17% vs 39%, respectively). The most common adverse events with IV levetiracetam in the multiple-dose phase were also somnolence (33% vs 17% placebo) and postural dizziness (25% vs 0% placebo). CONCLUSIONS: In these healthy subjects, single doses of levetiracetam 1,500 mg administered as a 15-minute IV infusion and as oral tablets were bioequivalent. General and local tolerability during multiple dosing were good. Steady state was reached within 48 hours. Despite the limitations of a study of short duration and small size conducted in healthy subjects, the findings suggest that use of a 15-minute IV infusion of levetiracetam should be further investigated.