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Warrack B.M.,Pharmaceutical Candidate Optimization Bioanalytical and Discovery Analytical science | Redding B.P.,United Road Services | Chen G.,Pharmaceutical Candidate Optimization Bioanalytical and Discovery Analytical science | Bolgar M.S.,Analytical and Bioanalytical Development
Analytical and Bioanalytical Chemistry | Year: 2013

PEGylation has been widely used to improve the biopharmaceutical properties of therapeutic proteins and peptides. Previous studies have used multiple analytical techniques to determine the fate of both the therapeutic molecule and unconjugated poly(ethylene glycol) (PEG) after drug administration. A straightforward strategy utilizing liquid chromatography-mass spectrometry (LC-MS) to characterize high-molecular weight PEG in biologic matrices without a need for complex sample preparation is presented. The method is capable of determining whether high-MW PEG is cleaved in vivo to lower-molecular weight PEG species. Reversed-phase chromatographic separation is used to take advantage of the retention principles of polymeric materials whereby elution order correlates with PEG molecular weight. In-source collisioninduced dissociation (CID) combined with selected reaction monitoring (SRM) or selected ion monitoring (SIM) mass spectrometry (MS) is then used to monitor characteristic PEG fragment ions in biological samples. MS provides high sensitivity and specificity for PEG and the observed retention times in reversed-phase LC enable estimation of molecular weight. This method was successfully used to characterize PEG molecular weight in mouse serum samples. No change in molecular weight was observed for 48 h after dosing. © Springer-Verlag Berlin Heidelberg 2012. Source


Narang A.S.,Drug Product Science and Technology | Badawy S.,Drug Product Science and Technology | Ye Q.,Analytical and Bioanalytical Development | Patel D.,Drug Product Science and Technology | And 11 more authors.
Pharmaceutical Research | Year: 2015

Purpose: Precipitation of weakly basic drugs in intestinal fluids can affect oral drug absorption. In this study, the implications of self-association of brivanib alaninate in acidic aqueous solution, leading to supersaturation at basic pH condition, on its solubility and oral absorption were investigated.Methods: Self-association of brivanib alaninate was investigated by proton NMR spectroscopy, surface tension measurement, dynamic light scattering, isothermal titration calorimetry, and molecular modeling. Drug solubility was determined in various pH media, and its tendency to supersaturate upon pH shift was investigated in buffered and biorelevant aqueous solutions. Pharmacokinetic modeling of human oral drug absorption was utilized for parameter sensitivity analyses of input variables.Results: Brivanib alaninate exhibited continuous, and pH- and concentration-dependent self-association. This phenomenon resulted in positive deviation of drug solubility at acidic pH and the formation of a stable supersaturated drug solution in pH-shift assays. Consistent with the supersaturation phenomenon observed in vitro, oral absorption simulations necessitated invoking long precipitation time in the intestine to successfully predict in vivo data.Conclusions: Self-association of a weakly basic drug in acidic aqueous solution can increase its oral absorption by supersaturation and precipitation resistance at the intestinal pH. This consideration is important to the selection of parameters for oral absorption simulation. © 2015 Springer Science+Business Media New York Source


Jiang H.,Analytical and Bioanalytical Development | Zeng J.,Analytical and Bioanalytical Development | Zheng N.,Analytical and Bioanalytical Development | Kandoussi H.,Analytical and Bioanalytical Development | And 4 more authors.
Analytical Chemistry | Year: 2011

Quantitative determination of drug concentrations in tissue homogenates via liquid chromatography-tandem mass spectrometry (LC-MS/MS) is commonly conducted using the standards and analytical quality controls (QCs) prepared in the same matrix (tissue homogenates), to keep the matrix and its effects consistent on the analytes during sample extraction and analysis. In this manuscript, we proposed to analyze tissue homogenate samples using an LC-MS/MS assay with the standards and analytical QCs prepared in plasma after tissue homogenate samples were appropriately diluted with plasma. BMS-650032 was used as a model compound, and its validated dog plasma assay was used for dog liver sample analyses. The tissue matrix effect was evaluated by diluting liver homogenate QCs with drug-free plasma at different dilution factors to determine the minimum required dilution factor (MRDF) at which tissue matrix has insignificant impact to the plasma assay. The percentage deviation of the measured concentration from the nominal concentration was used as an indicator of the tissue matrix effect. The results suggested that the tissue matrix effect was decreased as the plasma dilution factor increased. Based on the results of the tissue matrix effect evaluation, liver homogenate samples were analyzed after appropriate dilutions with plasma at the MRDF or greater dilution factors. The results confirmed that this approach generates accurate data, and the process is very convenient and economic. This approach has been used on the analyses of different tissues (liver and brain) and biofluid (bile) to support several drug development programs. © 2011 American Chemical Society. Source


Jiang H.,Analytical and Bioanalytical Development | Zeng J.,Analytical and Bioanalytical Development | Titsch C.,Analytical and Bioanalytical Development | Voronin K.,Bristol Myers Squibb | And 8 more authors.
Analytical Chemistry | Year: 2013

An LC-MS/MS assay was developed and fully validated for the simultaneous quantitation of two coadministered human monoclonal antibodies (mAbs), mAb-A and mAb-B of IgG4 subclass, in monkey serum. The total serum proteins were digested with trypsin at 50 C for 30 min after methanol denaturation and precipitation, dithiothreitol reduction, and iodoacetamide alkylation. The tryptic peptides were chromatographically separated with a C18 column (2.1 × 100 mm, 1.7 μm) with mobile phases of 0.1% formic acid in water and acetonitrile. Four peptides, a unique peptide for each mAb and two confirmatory peptides from different antibody domains, were simultaneously quantified by LC-MS/MS in the multiple reaction-monitoring mode. Stable isotopically labeled peptides with flanking amino acids on C-and N-terminals were used as internal standards to minimize the variability during sample processing and detection. The LC-MS/MS assay showed lower limit of quantitation (LLOQ) at 5 μg/mL for mAb-A and 25 μg/mL for mAb-B. The intra-and interassay precision (%CV) was within 10.0% and 8.1%, respectively, and the accuracy (%Dev) was within ±5.4% for all the peptides. Other validation parameters, including sensitivity, selectivity, dilution linearity, processing recovery and matrix effect, autosampler carryover, run size, stability, and data reproducibility, were all evaluated. The confirmatory peptides played a critical role in confirming quantitation accuracy and the integrity of the drugs in the study samples. The robustness of the LC-MS/MS assay and the data agreement with the ligand binding data demonstrated that LC-MS/MS is a reliable and complementary approach for the quantitation of coadministered antibody drugs. © 2013 American Chemical Society. Source

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