Safety, Pharmacokinetics, and Pharmacodynamics of ASP3662, a Novel 11β‐Hydroxysteroid Dehydrogenase Type 1 Inhibitor, in Healthy Young and Elderly Subjects

Inhibition of the enzyme 11β‐hydroxysteroid dehydrogenase type 1 (11β‐HSD1) represents a potential mechanism for improving pain conditions. ASP3662 is a potent and selective inhibitor of 11β‐HSD1. Two phase I clinical studies were conducted to assess the safety, tolerability, pharmacokinetics (PKs), and pharmacodynamics (PDs) of single and multiple ascending doses of ASP3662 in healthy young and elderly non‐Japanese and young Japanese subjects. Nonlinear, more than dose‐proportional PKs were observed for ASP3662 after single‐dose administration, particularly at lower doses (≤ 6 mg); the PKs at steady state were dose proportional, although the time to ASP3662 steady state was dose dependent at lower doses (≤ 2 mg). Similar PKs were observed among young Japanese, young non‐Japanese, and elderly non‐Japanese subjects. Specific inhibition of 11β‐HSD1 occurred after both single and multiple doses of ASP3662. A marked dissociation between PKs and PDs was observed after single but not multiple doses of ASP3662. ASP3662 was generally safe and well tolerated

Pharmacokinetics and safety of brivaracetam in neonates with repeated electroencephalographic seizures: A multicenter, open‐label, single‐arm study

Abstract Objective To evaluate the pharmacokinetics (PK), safety, and tolerability of brivaracetam (BRV) in neonates with repeated electroencephalographic seizures not controlled with previous antiseizure medications (ASMs). Methods Phase 2/3, multicenter, open‐label, single‐arm study (N01349/NCT03325439) in neonates with repeated electroencephalographic seizures (lasting ≥10 s) confirmed by video‐electroencephalography, and inadequate seizure control with at least one ASM. A screening period (up to 36 h) was followed by a 48‐h evaluation period during which patients received 0.5 mg/kg BRV twice daily (b.i.d) intravenously (IV). Patients who benefitted from BRV (investigator's opinion) could continue 0.5 mg/kg b.i.d (IV or oral solution) in an extension period. Outcomes included plasma concentrations of BRV following the first dose (primary), and incidence of treatment‐emergent adverse events (TEAEs). Results Six patients (median [range] postnatal age: 1.5 [1.0, 6.0] days) received ≥1 dose of BRV. All six patients completed the evaluation period; two entered and completed the extension period. Overall (evaluation and extension periods), three patients received one dose of 0.5 mg/kg BRV and three received more than one dose. The median (range) duration of exposure to BRV (IV and oral solution) was 1.5 (1.0, 29.0) days (n = 6). At 0.5–1, 2–4, and 8–12 h following IV BRV administration, the GeoMean (GeoCV) plasma concentrations of BRV were 0.53 mg/L (15.40% [n = 5]), 0.50 mg/L (28.20% [n = 6]), and 0.34 mg/L (13.20% [n = 5]), respectively. Individual and population BRV PK profiles were estimated, and individual PK parameters were calculated using Bayesian feedback. The observed concentrations were consistent with the predicted PK. Three patients experienced four TEAEs, none of which were considered related to BRV. Significance BRV plasma concentrations in neonates were consistent with data in older children receiving BRV oral solution, and with data from adults receiving a nominal IV dose of 25 mg b.i.d. BRV was well tolerated, with no drug‐related TEAEs reported. Plain Language Summary Few drugs are available to treat seizures in newborn babies. Brivaracetam is approved to treat focal‐onset seizures in children and adults in Europe (patients 2 years of age and older) and the United States (patients 1 month of age or older). In this study, six newborns with repeated seizures were treated with intravenous brivaracetam. The study doctors took samples of blood from the newborns and measured the levels of brivaracetam. The concentrations of brivaracetam in the newborns’ blood plasma were consistent with data from studies in older children and in adults. No brivaracetam‐related medical problems were reported

The variability in beta-cell function in placebo-treated subjects with type 2 diabetes: application of the weight-HbA1c-insulin-glucose (WHIG) model

Aim: The weight-glycosylated haemoglobin (HbA1C)-insulin-glucose (WHIG) model describes the effects of changes in weight on insulin sensitivity (IS) in newly diagnosed, obese subjects receiving placebo treatment. This model was applied to a wider population of placebo-treated subjects, to investigate factors influencing the variability in IS and β-cell function. Methods: The WHIG model was applied to the WHIG dataset (Study 1) and two other placebo datasets (Studies 2 and 3). Studies 2 and 3 consisted of nonobese subjects and subjects with advanced type 2 diabetes mellitus (T2DM). Body weight, fasting serum insulin (FSI), fasting plasma glucose (FPG) and HbA1c were used for nonlinear mixed-effects modelling (using NONMEM v7.2 software). Sources of interstudy variability (ISV) and potential covariates (age, gender, diabetes duration, ethnicity, compliance) were investigated. Results: An ISV for baseline parameters (body weight and β-cell function) was required. The baseline β-cell function was significantly lower in subjects with advanced T2DM (median difference: Study 2: 15.6%, P < 0.001; Study 3: 22.7%, P < 0.001) than in subjects with newly diagnosed T2DM (Study 1). A reduction in the estimated insulin secretory response in subjects with advanced T2DM was observed but diabetes duration was not a significant covariate. Conclusion: The WHIG model can be used to describe the changes in weight, IS and β-cell function in the diabetic population. IS remained relatively stable between subjects but a large ISV in β-cell function was observed. There was a trend towards decreasing β-cell responsiveness with diabetes duration, and further studies, incorporating subjects with a longer history of diabetes, are required