Summary:Purpose: The primary objective of this placebocontrolled 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 (≤4,000 mg infused over 15 min and ≤2,500 mg infused over 5 min) were primarily related to the CNS (dizziness, 52.8%; somnolence, 33.3%; fatigue, 11.1%; headache, 8.3%) and were consistent with the established safety profile for the oral formulation. Safety profiles were similar for each dose level of LEV and for both IV infusion rates, with no clear relation noted between incidence of adverse events and IV dose level or infusion rate. The pharmacokinetics of LEV administered by IV infusion was comparable across all dose groups and infusion rates. Respective geometric means (coefficient of variation) for 4,000 mg administered over 15 min and 2,500 mg infused over 5 min were maximum plasma concentration, 145 (24.6%) and 94.3 (36.2%) μg/ml; area under the plasma concentration-time curve, 1,239 (19.2%) and 585 (9.6%) μg/h/ml; terminal half-life, 8.0 (14.5%) and 7.0 (12.7%) h.Conclusions: LEV administered by IV infusion at dosages and/or infusion rates higher than those proposed was well tolerated in healthy subjects, and the pharmacokinetic profile was consistent with that for LEV administered orally.

BackgroundWomen 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.MethodsCRADLE (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.Results19 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.ConclusionWhen 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 numberNCT02154425; Results.

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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.

The pharmacokinetic-pharmacodynamic model for 24-hour ABPM can be used to estimate the concentration-effect relationship of antihypertensive drugs.