SAD/MAD studies

Exposure-response (ER) analysis has become an important tool to interpret QT data from TQT studies and has been used to predict QT effects in patients for the targeted indication, including patients with impaired clearance of the dmg (Garnett et al. 2008 Piotrovsky 2005). ER analysis has also been applied to QT data derived from early SAD/MAD studies. Since the doses in SAD studies are often escalated to MTD, high plasma levels often are obtained, which allows for the evaluation of potential ECG effects over a wide range of plasma concentrations. With increasing confidence in data derived from these types of studies, the relevant question as to whether early QT assessment can replace the TQT study has been raised (Darpo... 

The ICH E14 guidance requests that data are analyzed by timepoint, which means that a QTc effect (measured as the placebo-adjusted change-from-baseline AAQTc) exceeding 10 ms must be excluded at each post-dosing timepoint irrespective of the observed plasma levels of the drug. Formal power calculation using an assumption of SD of AQTc of 10-12 ms, which is the QTc variability typically observed with a semiautomated QT measurement techniques (see Table 1), shows that 60-90 subjects are required to achieve acceptable power (90 %) to exclude a 10 ms effect (Tsong et al. 2010). For standard SAD/MAD studies with... 

First-in-human studies (SAD MAD) Microdosing Human ADME Drug-drug interaction... 

Requirements for obtaining in vivo human metabolism information early in the development of an NCE and the opportunity to determine metabolite concentrations at steady state has persuaded several of the pharmaceutical companies to take advantage of the SAD and MAD studies to get a glimpse of the metabolites present in human plasma and urine [24], In SAD studies, urine (0-24 h) and blood samples (3-4 time points) can be collected from placebo- and NCE-dosed healthy volunteers from the top two or three dose groups. Since the volume of plasma samples from FIH studies are limited, one option is to use urine samples (pooled across subjects) to optimize/develop extraction, chromatographic, and MS conditions for metabolite detection activities. Once plasma extraction/reconstitution methods are optimized, pooled plasma from NCE- and placebo-dosed subjects are analyzed. LC-MS profiles of placebo-dosed subjects are used to eliminate matrix ions, dose formulation-related ions, and other background ions so that drug-related ions can be readily identified in the NCE-dosed samples. 

Although there are several benefits in detecting and characterizing metabolites in human SAD and MAD study samples, there are also several analytical shortcomings and caveats that need to be taken into considerations before using the FIH metabolism data to derive decision regarding disproportionate circulating metabolites. The major... 

SAD study plasma/urine methods k, MAD study plasma/urine... 

FIGURE 5.9 A proposed work flow for addressing metabolite in safety testing guidance and detecting and characterizing human metabolites in SAD and MAD studies. 

There is considerable interest in the coordination" and catalytic chemistries of these discrete clusters. Because of its high electron count, the hexaaquo ion [Ta6(p-Br)i2(OH2)6] has been used frequently for phase determination of isomorphous protein derivatives by SIR, MIR, SIRAS/MIRAS, and SAD/MAD methods in biomacromolecular crystallography. This use is growing as larger biomacromolecular structures and assemblies (e.g., membrane proteins, ribosomes, proteasomes) are studied. 

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