These data show that single doses of LY450139 up to 140 mg are accompanied by a dose-dependent plasma Abeta response. No response in CSF Abeta was apparent 4 hours after dosing.
AimsTo evaluate the pharmacokinetics and safety of once‐daily (QD) tadalafil in paediatric patients with pulmonary arterial hypertension (PAH) to establish an appropriate dose range for further research.MethodsThis was an open‐label, multicentre, international, multiple‐ascending‐dose study. Patients aged ≥2 years were enrolled into 1 of 3 cohorts based on body weight: heavy‐weight (≥40 kg), middle‐weight (25 to <40 kg), and light‐weight (<25 kg). Each patient received tadalafil QD for 10 weeks: 5 weeks at a low dose, then 5 weeks at a high dose. The doses for each cohort were intended to produce plasma tadalafil concentrations within the range produced by 5–10 mg (for the low dose) or 20–40 mg (for the high dose) of tadalafil in adults with PAH. Area under the plasma concentration–time curve during 1 dosing interval (AUCτ), maximum concentration, and apparent clearance were assessed throughout the trial, as were safety and tolerability.ResultsThe study enrolled 19 patients aged 2–17 years, weighing 9.9–76.0 kg. Tadalafil's median (range) steady‐state AUCτ at the high dose was 7243 (3131–13 088) ng•h/mL across all patients. Concentrations were higher in no bosentan‐treated patients than in bosentan‐treated patients, but both populations were within the range of respective adult patients taking 20–40 mg QD. Tadalafil had an acceptable safety profile consistent with the known safety profile of tadalafil in adults.ConclusionsTadalafil 40 mg QD for patients ≥40 kg, and 20 mg QD for patients <40 kg and aged ≥2 years, are suitable for further research in paediatric patients with PAH.
Study HighlightsWHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC? Bamlanivimab and etesevimab are potent neutralizing antibodies that target the spike protein of severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2).
WHAT QUESTION DID THIS STUDY ADDRESS? This study characterizes the pharmacokinetics (PKs) of bamlanivimab and etesevimab and the exposure-response relationship for reduction in viral load in patients with coronavirus disease 2019 (COVID-19). The study identified the optimal doses and investigated the impact of various demographic factors that could affect therapeutic response to the neutralizing antibodies.
When administered as a per-kilogram single dose of solanezumab, PK and pharmacodynamics (plasma total Aβ1-40 concentration) in the Japanese patients with AD were comparable with those in the white patients with AD. In addition, solanezumab was generally well tolerated in both Japanese and white patients at all dose levels.
IntroductionSolanezumab treatment was previously shown to significantly increase total (bound + unbound) cerebrospinal fluid (CSF) levels of amyloid β (Aβ)1–40 and Aβ1–42 in patients with mild to moderate Alzheimer's disease dementia yet did not produce meaningful cognitive effects. This analysis assessed solanezumab's central nervous system target engagement by evaluating changes in CSF total and free Aβ isoforms and their relationship with solanezumab exposure.MethodsCSF Aβ isoform concentrations were measured in patients with mild Alzheimer's disease dementia from a pooled EXPEDITION + EXPEDITION2 population and from EXPEDITION3. CSF solanezumab concentrations were determined from EXPEDITION3.ResultsSolanezumab produced statistically significant increases in CSF total Aβ isoforms versus placebo, which correlated with CSF solanezumab concentration. Inconsistent effects on free Aβ isoforms were observed. Solanezumab penetration into the central nervous system was low.DiscussionSolanezumab administration engaged the central molecular target, and molar ratio analyses demonstrated that higher exposures may further increase CSF total Aβ concentrations.
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