Year: 2010
Type: letter
Abstract: We appreciate Dr Albright and Dr Raybon's interest in the analysis of “A Gamma-Secretase Inhibitor Decreases Amyloid-Beta Production in the Central Nervous System.”1 In their letter, they have challenged 2 aspects related to how the data from our study were analyzed. The first is related to how area under the curve (AUC) calculations are used to quantify the level of inhibition of amyloid-beta (Aβ) synthesis, and the second is how the placebo data from the study should be interpreted. We agree that Aβ synthesis and clearance are occurring simultaneously, even for the newly synthesized and labeled Aβ. However, the process that is dominant, and thus primarily affects the shape of the labeled Aβ concentration versus time curve, changes over the 36-hour period that data were collected. During the early portion of the 36-hour period the dominant process is synthesis, and during the later portion of the 36-hour period the dominant process is clearance. We have excluded the middle 12-hour period from our analyses for exactly the reason Albright and Raybon have raised; during this time period, the synthesis and clearance of labeled Aβ are competing processes, and it would be difficult with simple AUC analyses to separately quantify the 2 processes. Our justifications for using the first 12 hours to quantify inhibition of Aβ synthesis are (1) LY450139 is only present at significant inhibitory concentrations during this time period; and (2) labeled leucine was only infused for 9 hours, and therefore would not be available to be incorporated into newly synthesized Aβ for times much longer than 9 hours. Albright and Raybon have used an analogy to traditional pharmacokinetics to justify their AUC analysis approach, and we can extent this analogy to justify why their approach is not appropriate for our study. Pharmacokineticists sometimes use the AUC of the initial portion of a concentration time curve to better understand the rate of absorption, and they use the full AUC of the concentration time curve to understand extent of absorption. A simple example of this is for drugs where the rate of absorption is significantly affected by food, but the extent of absorption and thus total AUC is only slightly affected. In this situation, only the initial AUC is significantly altered, and using the total AUC to interpret how much food inhibited the rate of absorption would lead to erroneous conclusions. The same is true for our study as it relates to using the most appropriate AUC to quantify inhibition of the rate of Aβ synthesis. The analysis methods that we have used in our study have been established over many years of isotope tracer research.2, 3 Newer methodologies that apply more complex analysis methods, such as mechanistic and physiologically based modeling, will likely be used in the future to better quantify complex processes such as Aβ trafficking. The second aspect of the study challenged by Albright and Raybon is how the placebo data were utilized. The study was designed and implemented as a blinded placebo-controlled study of the effects of treatment on Aβ production and concentration. The ad hoc proposal to ignore the placebo group and compare Aβ changes to baseline is not compatible with the study design. As demonstrated in this and other studies,4, 5 baseline cerebrospinal fluid (CSF) Aβ concentrations are highly dynamic within subjects and variable between subjects. Therefore, there is no stable baseline Aβ concentration due to baseline fluctuations. Further, the placebo group's6C13-labeled Aβ production and clearance rates were similar to previous studies,6 whereas those treated with drug had clearly decreased Aβ production while having no difference in Aβ clearance. This demonstrates that the groups were well matched for Aβ metabolism, and that the effect on Aβ production was due to the drug. The effects of LY450139 on Aβ production are the most accurate and direct measurement in humans to date based on well-established research utilizing isotope tracers. Enzyme-linked immunosorbent assay (ELISA) CSF Aβ concentration measurements are confounded by variability and do not directly assess Aβ production, which is the pharmacodynamic target of gamma-secretase inhibitors. Further, Aβ concentration measured only by ELISA is affected by changes in total Aβ pools due to Aβ kinetics and likely underestimates the pharmacodynamic effect in single-dose drug studies. The magnitude of effect of a gamma secretase inhibitor necessary to produce a clinical effect is currently unknown. Direct measurement of Aβ production using the SILK technique provides a highly quantitative measure that can be compared to the clinical outcomes of the ongoing phase III studies of LY450139. Based on these initial comparisons, this technique can be subsequently applied even more effectively to evaluate future compounds that affect Aβ production. Randall J. Bateman*, Eric R. Siemers , Kwasi G. Mawuenyega*, Wendy C. Sigurdson*, Kevin E. Yarasheski , Stuart W. Friedrich , Ron B. DeMattos , Patrick C. May , Steven M. Paul , David M. Holtzman*, * Department of Neurology, Washington University School of Medicine, St. Louis, MO, Eli Lilly & Company, Indianapolis, IN, Division of Endocrinology, Metabolism, and Lipid Research, Washington University School of Medicine, St. Louis, MO.
Source: Annals of Neurology
DOI: 10.1002/ana.21930
Institutions: Washington University in St. Louis, Eli Lilly (United States)
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
Funder: Eli Lilly and Company
OpenAlex ID: W4249774137