Due to varying doses and a lack of statistical precision, this Class II ascending dose trial provides insufficient evidence to support or refute a benefit of bapineuzumab.

No abstract

Background Amyloid-related imaging abnormalities (ARIA) have been reported in Alzheimer’s disease (AD) patients treated with bapineuzumab, a humanized monoclonal antibody to amyloid-β. ARIA includes MRI signal abnormalities suggestive of vasogenic edema and sulcal effusions (ARIA-E) and hemosiderin deposits (ARIA-H). A better understanding of the incidence and risk factors for ARIA may further the development of amyloid-modifying treatments for AD. Methods Two neuroradiologists independently reviewed (kappa=0.76) and then reached consensus reads on over 2500 FLAIR-MRIs from 262 participants in three phase 2 studies of bapineuzumab. Subjects (n=210) were included in risk analyses if they had no evidence of ARIA-E on pre-treatment MRI, received bapineuzumab, and had at least one post-treatment MRI. Findings 36/210 (17%) subjects developed ARIA-E during treatment; 28 of these 36 (78%) did not report associated symptoms. Adverse events reported in 8 symptomatic patients included headache, confusion, neuropsychiatric and gastrointestinal symptoms. 15/36 of the ARIA-E cases (42%) were detected only on central review. 13/15 received additional infusions while ARIA-E was present, without any associated symptoms reported. ARIA-E incidence increased with bapineuzumab dose (Hazard Ratio [HR] 2.24 per mg/kg increase in dose; p<0·001) and with APOE ε4 allele number (HR 2.55 per allele; p<0·001). Interpretation ARIA appears to represent a spectrum of imaging findings with variable clinical correlates, with some cases remaining asymptomatic even when treated through ARIA-E. The increased risk of ARIA with APOE ε4 and bapineuzumab dose, and the time course in relation to dosing, is consistent with alterations in vascular amyloid burden.

Response surfaces can describe anesthetic interactions, even those between agonists, partial agonists, competitive antagonists, and inverse agonists. Application of response-surface methodology permits characterization of the full concentration-response relation and therefore can be used to develop practical guidelines for optimal drug dosing.

Computer-controlled infusion pumps incorporating an internal model of drug pharmacokinetics can rapidly achieve and maintain constant drug concentrations in the plasma. Although these pumps offer more accurate titration of intravenous drugs than is possible with simple boluses or constant rate infusions, the choice of the plasma as the target site is arbitrary. The plasma is not the site of drug effect for most drugs. This manuscript describes two algorithms for calculation of the infusion rates necessary for a computer-controlled infusion pump to rapidly achieve, and then maintain, the desired target concentration at the site of drug effect rather than in the plasma.

Objective: To evaluate the effects of bapineuzumab on brain b-amyloid (Ab) burden using 11 C-Pittsburgh compound B ( 11 C-PiB)-PET.Methods: Two phase 3 clinical trials, 1 each in apolipoprotein APOE e4 carriers and noncarriers,were conducted in patients with mild to moderate Alzheimer disease dementia. Bapineuzumab, an anti-Ab monoclonal antibody, or placebo, was administered by IV infusion every 13 weeks for 78 weeks. PET substudies assessed change in brain fibrillar Ab over 71 weeks using an 11 C-PiB-PET standardized uptake value ratio (SUVr) global cortical average (GCA) comprising the average SUVr from 5 cortical regions of interest with cerebellar gray matter as the reference region. Bapineuzumab, a humanized monoclonal antibody targeting the N-terminus of b-amyloid (Ab), was recently evaluated in phase 3 trials for the treatment of mild to moderate Alzheimer disease (AD) dementia. As part of those investigations, brain volumetric MRI, brain amyloid PET imaging, and CSF sampling were performed in biomarker substudies. The primary aim of the substudies was to assess the pharmacologic effects of bapineuzumab on AD CNS biomarkers. The PET substudy used 11 C-Pittsburgh compound B ( 11 C-PiB)-PET as a measure of brain fibrillar Ab.1 Differences in the incidence of amyloid-related imaging abnormalities (ARIA) and potential efficacy signals had been seen between participants treated with bapineuzumab who were APOE e4 carriers and noncarriers in phase 2 studies 2-4 ; therefore, separate clinical trials for APOE e4 carriers (Study 302) and noncarriers (Study 301) were conducted in phase 3. The primary clinical and biomarker endpoint results of these trials were recently All authors contributed equally to this work.

T(peak) is a useful pharmacodynamic parameter and can be used to link separate pharmacokinetic and pharmacodynamic studies. This addresses a common difficulty in clinical pharmacology simulation and control problems, where there is usually a wide choice of pharmacokinetic models but only one or two published pharmacokinetic-pharmacodynamic models. The results will be immediately applicable to target-controlled anesthetic infusion systems, where linkage of separate pharmacokinetic and pharmacodynamic parameters into a single model is inherent in several target-controlled infusion designs.

These data suggest that vascular leakage events, such as microhemorrhage, may be related to the removal of vascular Aβ. With continued treatment, this initial susceptibility period is followed by restoration of vascular morphology and reduced vulnerability to further vascular leakage events. The data collectively suggested a vascular amyloid clearance model of ARIA, which accounts for the currently known risk factors for the incidence of ARIA in clinical studies.