Publications by authors named "Wenkui Li"

69 Publications

Critical considerations of matrix selection in LC-MS bioanalysis for toxicokinetic and pharmacokinetic assessment in drug development.

Bioanalysis 2021 Apr 17;13(8):605-608. Epub 2021 Mar 17.

Pharmacokinetic Sciences, Novartis Institutes for BioMedical Research, East Hanover, NJ 07936, USA.

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http://dx.doi.org/10.4155/bio-2020-0319DOI Listing
April 2021

The effectiveness of quality control samples in pharmaceutical bioanalysis.

Bioanalysis 2021 Feb 4;13(3):135-145. Epub 2021 Feb 4.

Bristol-Myers Squibb Co. Princeton, NJ 08540, USA.

The use of quality control (QC) samples in bioanalysis is well established and consistent with regulatory guidance. However, a systematic evaluation of whether QC samples serve the intended purpose of improving data quality has not been undertaken. The Translational and ADME Sciences Leadership Group (TALG) of the International Consortium for Innovation and Quality in Pharmaceutical Development (IQ) conducted an evaluation to assess whether closer agreement is observed when comparing pharmacokinetic data from two passed runs, than when comparing data from failed and passed (retest) runs. Analysis of data collected across organizations, molecular types and analytical platforms, revealed that bioanalytical methods are very reproducible; and that QC samples improve the overall quality of pharmacokinetic concentration data and justifies their continued use.
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http://dx.doi.org/10.4155/bio-2020-0265DOI Listing
February 2021

2020 White Paper on Recent Issues in Bioanalysis: BMV of Hybrid Assays, Acoustic MS, HRMS, Data Integrity, Endogenous Compounds, Microsampling and Microbiome ( - Recommendations on Industry/Regulators Consensus on BMV of Biotherapeutics by LCMS, Advanced Application in Hybrid Assays, Regulatory Challenges in Mass Spec, Innovation in Small Molecules, Peptides and Oligos).

Bioanalysis 2021 Feb 20;13(4):203-238. Epub 2021 Jan 20.

Merck, West Point, PA, USA.

The 14 edition of the Workshop on Recent Issues in Bioanalysis (14 WRIB) was held virtually on June 15-29, 2020 with an attendance of over 1000 representatives from pharmaceutical/biopharmaceutical companies, biotechnology companies, contract research organizations, and regulatory agencies worldwide. The 14 WRIB included three Main Workshops, seven Specialized Workshops that together spanned 11 days in order to allow exhaustive and thorough coverage of all major issues in bioanalysis, biomarkers, immunogenicity, gene therapy, cell therapy and vaccine. Moreover, a comprehensive vaccine assays track; an enhanced cytometry track and updated Industry/Regulators consensus on BMV of biotherapeutics by Mass Spectrometry (hybrid assays, LCMS and HRMS) were special features in 2020. As in previous years, this year's WRIB continued to gather a wide diversity of international industry opinion leaders and regulatory authority experts working on both small and large molecules to facilitate sharing and discussions focused on improving quality, increasing regulatory compliance and achieving scientific excellence on bioanalytical issues. This 2020 White Paper encompasses recommendations emerging from the extensive discussions held during the workshop and is aimed to provide the Global Bioanalytical Community with key information and practical solutions on topics and issues addressed, in an effort to enable advances in scientific excellence, improved quality and better regulatory compliance. Due to its length, the 2020 edition of this comprehensive White Paper has been divided into three parts for editorial reasons. This publication covers the recommendations on (Part 1) Hybrid Assays, Innovation in Small Molecules, & Regulated Bioanalysis. Part 2A (BAV, PK LBA, Flow Cytometry Validation and Cytometry Innovation), Part 2B (Regulatory Input) and Part 3 (Vaccine, Gene/Cell Therapy, NAb Harmonization and Immunogenicity) are published in volume 13 of Bioanalysis, issues 5, and 6 (2021), respectively.
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http://dx.doi.org/10.4155/bio-2020-0324DOI Listing
February 2021

Accelerating charge transfer to enhance H evolution of defect-rich CoFeO by constructing a Schottky junction.

Chem Commun (Camb) 2020 Nov;56(90):14019-14022

State Key Laboratory of Powder Metallurgy, Central South University, Changsha 410083, China.

We demonstrate a charge transfer boosted hydrogen (H2) evolution of transition metal oxides via a Schottky junction. The FeNi and metallic defect-rich CoFe2O4 (DCF) as well as semiconducting nitrogen-doped carbon (NC), named as FeNi/DCF/NC, possessed only 6.5% charge transfer resistance of DCF. Theoretical calculations indicate that the enhanced electron movement happened from FeNi/DCF to NC. The H2 evolution activity of FeNi/DCF/NC showed 5.8-fold improvement compared to that of DCF at the overpotential of 400 mV in 1.0 M KOH. This work provides an effective way to enhance the electrocatalytic activity of oxides for the H2 evolution reaction and related reactions.
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http://dx.doi.org/10.1039/d0cc05656aDOI Listing
November 2020

Dixon's Q-test and Student's t-test to assess analog internal standard response in nonregulated LC-MS/MS bioanalysis.

Bioanalysis 2020 Nov 16;12(21):1535-1543. Epub 2020 Oct 16.

NIBR, PK Sciences Bioanalytics, East Hanover, NJ 07936, USA.

In bioanalytical assays, analyte response is normalized to an internal standard response. When the internal standard works well, it compensates for processing and detection variability. However, in case the internal standard introduces additional variability, due to addition errors or other issues, scientists need to identify this. A new method, using a Q-test for outliers and a t-test to compare internal standard response from different sample types, is applied to 15 cases. The results show that the Q-test/t-test, which uses confidence level rather than arbitrary cut-points, is more discerning of deviations compared with widely used methods. This work may improve the quality of and rationale for the internal standard response monitoring method.
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http://dx.doi.org/10.4155/bio-2020-0207DOI Listing
November 2020

Postcardiac injury syndrome, peripheral hematoma of ascending aorta, and cerebral infarction after PCI: a case report.

BMC Cardiovasc Disord 2020 07 3;20(1):317. Epub 2020 Jul 3.

Department of Cardiology, Yijishan Hospital of Wannan Medical College, Wuhu, China.

Background: Postcardiac injury syndrome (PCIS) is an inflammatory response syndrome characterized by pericardial effusion with or without pleural effusion; however, serious PCIS with peripheral hematoma of the ascending aorta and acute cerebral infarction after percutaneous coronary intervention (PCI) have not been reported.

Case Presentation: This article reports a very rare case of a 40-year-old patient who developed acute pericardial and pleural effusions (both bloody), acute respiratory distress, peripheral hematoma of the ascending aorta, and acute cerebral infarction after PCI. The patient's ECG showed bow-back downward ST elevation in leads I, II, III, and V4-V6. A blood test showed significant increases in eukaryotic-cell count, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP). Echocardiography and pulmonary artery computed tomography angiography (CTA) showed a large amount of pericardial effusion and pleural effusion. CTA of the thoracic and abdominal aorta showed a peripheral hematoma of the ascending aorta. A cranial computed tomography (CT) showed cerebral infarction anterior to the anterior horn of the right ventricle. After tracheal intubation, ventilator breathing support, pericardial and pleural drainage, and adrenocortical steroid (prednisone) treatment, he gradually recovered and was discharged 20 days later.

Conclusion: We report the management of a case of serious PCIS with peripheral hematoma of the ascending aorta and acute cerebral infarction after PCI. Early diagnosis, early differential diagnosis, and early use of steroid therapy are the key in treating PCIS.
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http://dx.doi.org/10.1186/s12872-020-01608-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7333298PMC
July 2020

Application of tail vein serial microsampling for plasma or dried plasma spots in toxicokinetic assessment in rats using acetaminophen as the model compound.

Biomed Chromatogr 2020 Oct 6;34(10):e4917. Epub 2020 Aug 6.

Pharmacokinetic Sciences, Novartis Institutes for BioMedical Research, East Hanover, NJ, USA.

In the current study, two groups of rats (five per group) were administered a single oral dose of 500 mg/kg acetaminophen. For toxicokinetic assessment, the Group 1 animals were bled via conventional sparse (two animals/time point) sublingual vein bleeding (~0.5 ml) with anesthesia, while the Group 2 animals were bled via serial tail vein microsampling (~0.075 ml) without anesthesia. All collected blood was processed for plasma. Each Group 2 plasma sample (~30 μl) was divided into 'wet' and 'dried' (dried plasma spots). All plasma samples were analyzed by LC-MS/MS for acetaminophen and its major metabolites acetaminophen glucuronide and acetaminophen sulfate. In addition, plasma and urine samples were collected for analysis of corticosterone and creatinine to assess stress levels. Comparable plasma exposure to acetaminophen and its two metabolites was observed in the plasma obtained via conventional sparse sublingual vein bleeding and serial tail vein microsampling and between the 'wet' and 'dried' plasma obtained by the latter. Furthermore, comparable corticosterone levels or corticosterone/creatinine ratios between the two groups suggested that serial microsampling without anesthesia did not increase the levels of stress as compared with conventional sampling with anesthesia, confirming the utility of microsampling for plasma or dried plasma spots in rodent toxicokinetic assessment.
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http://dx.doi.org/10.1002/bmc.4917DOI Listing
October 2020

Evaluation, identification and impact assessment of abnormal internal standard response variability in regulated LC-MS bioanalysis.

Bioanalysis 2020 Apr 30;12(8):545-559. Epub 2020 Apr 30.

Pharmacokinetic Sciences, Novartis Institutes for BioMedical Research, East Hanover, NJ 07936, USA.

Internal standard (IS) plays an important role in LC-MS bioanalysis by compensating for the variability of the analyte of interest in bioanalytical workflow. Due to the complexity of biological sample compositions and bioanalytical processes, a certain level of IS response variability across a run or a study is anticipated. However, an extensive variability may raise doubts to the accuracy of the measured results and also suggest nonoptimal analytical method. In this current paper, recent publications and guidelines regarding IS response in LC-MS bioanalysis were thoroughly reviewed with focus on the evaluation, identification and impact assessment of 'abnormal' IS response variability. A systematic decision tree was proposed to facilitate investigation into abnormal IS response variability after each run.
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http://dx.doi.org/10.4155/bio-2020-0058DOI Listing
April 2020

AKAP5 anchors PKA to enhance regulation of the HERG channel.

Int J Biochem Cell Biol 2020 05 12;122:105741. Epub 2020 Mar 12.

Department of Cardiology, Yijishan Hospital of Wannan Medical College, Wuhu, China. Electronic address:

The activation of the β-adrenergic receptor (β-AR) regulates the human ether a-go-go-related gene (HERG) channel via protein kinase A (PKA), which in turn induces lethal arrhythmia in patients with long QT syndromes (LQTS). However, the role of A-kinase anchoring proteins (AKAPs) in PKA's regulation of the HERG channel and its molecular mechanism are not clear. Here, HEK293 cells were transfected with the HERG gene alone or co-transfected with HERG and AKAP5 using Lipofectamine 2000. Western blotting was performed to determine HERG protein expression, and immunofluorescence and immunoprecipitation were used to assess the binding and cellular colocalization of HERG, AKAP5, and PKA. The HEK293-HERG and HEK293-HERG + AKAP5 cells were treated with forskolin at different concentrations and different time. HERG protein expression significantly increased under all treatment conditions (P < 0.001). The level of HERG protein expression in HEK293-HERG + AKAP5 cells was higher than that observed in HEK293-HERG cells (P < 0.001). Immunofluorescence and immunoprecipitation indicated that HERG bound to PKA and AKAP5 and was colocalized at the cell membrane. The HERG channel protein, AKAP5, and PKA interacted with each other and appeared to form intracellular complexes. These results provide evidence for a novel mechanism which AKAP5 anchors PKA to up-regulate the HERG channel protein.
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http://dx.doi.org/10.1016/j.biocel.2020.105741DOI Listing
May 2020

Spleen associated immune-response mediates brain-heart interaction after intracerebral hemorrhage.

Exp Neurol 2020 05 24;327:113209. Epub 2020 Jan 24.

Department of Neurology, Henry Ford Hospital, Detroit, MI 48202, USA. Electronic address:

Background And Purpose: Intracerebral hemorrhage (ICH) patients frequently encounter cardiovascular complications which may contribute to increased mortality and poor long term outcome. ICH induces systemic oxidative stress and activates peripheral immune responses which are involved in the pathological cascade leading to cardiac dysfunction and heart failure after ICH. We have previously reported that ICH induces progressive cardiac dysfunction in mice without primary cardiac diseases. In this study, we have investigated the role of immune response in mediating cardiac dysfunction post ICH in mice.

Methods: Adult male C57BL/6 J mice were randomly assigned to the following groups (n = 8/group): 1) sham control; 2) ICH; 3) splenectomy with ICH (ICH + Spx); 4) splenectomy alone (Spx). Echocardiography was performed at 7 and 28 days after ICH. A battery of neurological and cognitive tests were performed. Flow cytometry, western blot and immunostaining were used to test mechanisms of ICH induced cardiac dysfunction.

Results: Compared to sham control mice, Spx alone does not induce acute (7 day) or chronic (28 day) cardiac dysfunction. ICH induces significant neurological and cognitive deficits, as well as acute and chronic cardiac dysfunction compared to sham control mice. Mice subjected to ICH + Spx exhibit significantly improved neurological and cognitive function compared to ICH mice. Mice with ICH + Spx also exhibit significantly improved acute and chronic cardiac function compared to ICH mice indicated by increased left ventricular ejection fraction (LVEF) and left ventricular fractional shortening (LVFS), decreased cardiac fibrosis, decreased cardiomyocyte hypertrophy, decreased cardiac infiltration of immune cells and decreased expression of inflammatory factor and oxidative stress in the heart.

Conclusions: Our study demonstrates that splenectomy attenuates ICH-induced neurological and cognitive impairment as well as ICH-induced cardiac dysfunction in mice. Inflammatory cell infiltration into heart and immune responses mediated by the spleen may contribute to ICH-induce acute and chronic cardiac dysfunction and pathological cardiac remodeling.
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http://dx.doi.org/10.1016/j.expneurol.2020.113209DOI Listing
May 2020

Recommendations and best practices for calibration curves in quantitative LC-MS bioanalysis.

Bioanalysis 2019 Aug;11(15):1375-1377

Pharmacokinetic Sciences, Novartis Institutes for BioMedical Research, East Hanover, NJ 07936, USA.

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http://dx.doi.org/10.4155/bio-2019-0149DOI Listing
August 2019

Long noncoding RNA HAS2-AS1 promotes tumor progression in glioblastoma via functioning as a competing endogenous RNA.

J Cell Biochem 2020 01 5;121(1):661-671. Epub 2019 Aug 5.

Department of Neurology, Tianjin Neurological Institute, Key Laboratory of Post-Neurotrauma Neurorepair and Regeneration in Central Nervous System, Ministry of Education, Tianjin, China.

Glioblastoma multiforme (GBM) is a refractory tumor with poor prognosis and requires more effective treatment regimens. It has been confirmed that long noncoding RNAs (lncRNAs) substantially regulate various human disease including GBM. However, the biological roles and its underlying molecular mechanisms still need to be further investigated. In this study, the biological function and potential molecular mechanism of lncHAS2-AS1 in GBM were explored. It was discovered that HAS2-AS1 was elevated in glioma tissues and correlated with the prognosis of patients with glioma. Reduction of HAS2-AS1 suppressed the migration and invasion in vitro and in vivo. The transcription factor STAT1 could raise HAS2-AS1 by binding to its promoter region. Besides, HAS2-AS1 could adjust PRPS1 via sponging miR-608 in a direct manner. On the whole, the results of this study evidence that HAS2-AS1 is an oncogene and a potential therapeutic target for GBM.
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http://dx.doi.org/10.1002/jcb.29313DOI Listing
January 2020

Edible fungi-assisted harvesting system for efficient microalgae bio-flocculation.

Bioresour Technol 2019 Jun 9;282:325-330. Epub 2019 Mar 9.

Center for Biorefining, and Bioproducts and Biosystems Engineering Department, University of Minnesota, 1390 Eckles Ave, Saint Paul, MN 55108, USA. Electronic address:

Conventional flocculants, commonly used to improve harvesting efficiency, can contaminate the broth and cause microalgae not suitable for food or feed production. In the present study, Pleurotus ostreatus, an edible fungal strain, was developed to improve the harvesting efficiency of microalgae. The results show that Pleurotus ostreatus pellets cultured under 100 rpm agitation resulted in higher harvesting efficiency than pellets cultured under 0 rpm and 150 rpm agitation. Lower pH of the Chlorella sp. suspension resulted in higher harvesting efficiency. The maximum recovery efficiency reached 64.86% in 150 mins. The above process could be used to achieve low cost, flocculant-free harvesting of microalgae as feedstock for feed or food production.
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http://dx.doi.org/10.1016/j.biortech.2019.03.033DOI Listing
June 2019

Highly selective and sensitive LC-MS/MS quantification of a therapeutic protein in human serum using immunoaffinity capture enrichment.

J Chromatogr B Analyt Technol Biomed Life Sci 2018 Nov 2;1100-1101:83-90. Epub 2018 Oct 2.

Pharmacokinetic Sciences-Safety & ADME Bioanalysis, Novartis Institutes for BioMedical Research, One Health Plaza, East Hanover, NJ 07936, USA.

We report the development, validation and application of a liquid chromatography-tandem mass spectrometry (LC-MS/MS) bioanalytical method for the determination of a recombinant protein drug candidate, NVS001, in human serum. A unique surrogate peptide, IPAETTIYNR (IPA), was identified to distinguish NVS001 from its endogenous counterpart, i.e., the full length and the C-terminal of protein X in LC-MS/MS. The selection of IPA for the LC-MS/MS determination of NVS001 was supported by the absence of peak responses due to endogenous components in the LC-MS/MS chromatograms of the extracted blank human serum samples. The optimal chromatographic separation of IPA from the extracted matrix components was achieved on a Waters Cortecs C (100 × 2.1 mm, 2.7 μm) column using gradient elution with a run cycle time of approximately 7.5 min. The mobile phases were water containing 0.1% formic acid (mobile phase A) and acetonitrile containing 0.1% formic acid (mobile phase B). The method was validated for specificity, sensitivity, matrix effect, recovery, linearity, accuracy and precision, dilution integrity, and stability. The validated assay dynamic range was 10.0 to 1000 ng/mL using a 50 μL sample volume. The accuracy and precision for the LLOQ (10.0 ng/mL) sample results were within ±9.2% bias and ≤6.0% CV, respectively. From the intra-day and inter-day assay performance evaluations, the precision of the QC sample (30, 500 and 750 ng/mL) results were ≤3.5% CV and the accuracy within ±3.3% bias, respectively. An additional assessment of incurred sample reanalysis (ISR) was conducted to demonstrate the ruggedness and robustness of the assay method. The validated method was successfully implemented in support of a first-in-human study.
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http://dx.doi.org/10.1016/j.jchromb.2018.09.040DOI Listing
November 2018

Effect of Fluconazole Coadministration and CYP2C9 Genetic Polymorphism on Siponimod Pharmacokinetics in Healthy Subjects.

Clin Pharmacokinet 2019 03;58(3):349-361

Novartis Institutes for BioMedical Research (NIBR), 4002, Basel, Switzerland.

Objectives: The aim of this study was to assess the pharmacokinetics (PK) and safety/tolerability of siponimod in healthy subjects when coadministered with (1) the moderate cytochrome P450 (CYP) 2C9 and CYP3A inhibitor fluconazole (Study A), and (2) with three different CYP2C9 genotype variants (Study B).

Methods: Study A was an open-label, single-dose study comprising periods 1 (14 days; day 1: siponimod 4 mg) and 2 (20 days; day 1: fluconazole 200 mg twice daily; days 2-19: fluconazole 200 mg once daily; day 3: siponimod 4 mg) in healthy subjects (n = 14) with the wild-type CYP2C9 genotype (CYP2C9*1/*1). Study B was a multicentre, open-label study comprising parts 1 (day 1: siponimod 0.25 mg once daily in the CYP2C9*1/*1, CYP2C9*2/*3 and CYP2C9*3/*3 genotypes) and 2 (days 1-2: 0.25 mg once daily; day 3: 0.5 mg once daily in the CYP2C9*2/*3 and CYP2C9*3/*3 genotypes only) in healthy subjects with polymorphic variants of CYP2C9 (n = 24). Pharmacokinetic parameters were calculated using noncompartmental methods.

Results: In Study A, coadministration with fluconazole produced an approximately twofold increase in mean area under the curve (AUC) versus siponimod alone (from 1110 to 2160 h*ng/mL), and an increase in maximum plasma concentration (C; from 31.2 to 34.0 ng/mL) and elimination half-life (T; from 40.6 to 61.6 h). In Study B, the AUCs of siponimod were approximately two to fourfold greater in subjects with the CYP2C9*2/*3 and CYP2C9*3/*3 genotypes, with a minor increase in C versus the CYP2C9*1/*1 genotype. The mean T was prolonged in the CYP2C9*2/*3 (51 h) and CYP2C9*3/*3 (126 h) genotypes versus the CYP2C9*1/*1 (28 h) genotype. Siponimod did not result in increased adverse events in healthy subjects in both studies.

Conclusions: Changes in siponimod PK, when coadministered with fluconazole at steady-state and in subjects with different CYP2C9 genotypes, indicate that the reduced CYP2C9 enzymatic activity does not affect the absorption phase of siponimod but prolongs the elimination phase. These results confirm the relevance of CYP2C9 activity on siponimod metabolism in humans.
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http://dx.doi.org/10.1007/s40262-018-0700-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6373376PMC
March 2019

Metabolism and Disposition of Siponimod, a Novel Selective S1P/S1P Agonist, in Healthy Volunteers and In Vitro Identification of Human Cytochrome P450 Enzymes Involved in Its Oxidative Metabolism.

Drug Metab Dispos 2018 07 7;46(7):1001-1013. Epub 2018 May 7.

PK-Sciences, Novartis Pharma AG, Basel, Switzerland (U.G., Y.J., R.N., W.L., K.S., S.A.-S., E.L., H.B., A.D.J., A.M., G.C., A.G.), and PRA Health Sciences, Raleigh, North Carolina (S.P.M.).

Siponimod, a next-generation selective sphingosine-1-phosphate receptor modulator, is currently being investigated for the treatment of secondary progressive multiple sclerosis. We investigated the absorption, distribution, metabolism, and excretion (ADME) of a single 10-mg oral dose of [C]siponimod in four healthy men. Mass balance, blood and plasma radioactivity, and plasma siponimod concentrations were measured. Metabolite profiles were determined in plasma, urine, and feces. Metabolite structures were elucidated using mass spectrometry and comparison with reference compounds. Unchanged siponimod accounted for 57% of the total plasma radioactivity (area under the concentration-time curve), indicating substantial exposure to metabolites. Siponimod showed medium to slow absorption (median : 4 hours) and moderate distribution (Vz/F: 291 l). Siponimod was mainly cleared through biotransformation, predominantly by oxidative metabolism. The mean apparent elimination half-life of siponimod in plasma was 56.6 hours. Siponimod was excreted mostly in feces in the form of oxidative metabolites. The excretion of radioactivity was close to complete after 13 days. Based on the metabolite patterns, a phase II metabolite (M3) formed by glucuronidation of hydroxylated siponimod was the main circulating metabolite in plasma. However, in subsequent mouse ADME and clinical pharmacokinetic studies, a long-lived nonpolar metabolite (M17, cholesterol ester of siponimod) was identified as the most prominent systemic metabolite. We further conducted in vitro experiments to investigate the enzymes responsible for the oxidative metabolism of siponimod. The selective inhibitor and recombinant enzyme results identified cytochrome P450 2C9 (CYP2C9) as the predominant contributor to the human liver microsomal biotransformation of siponimod, with minor contributions from CYP3A4 and other cytochrome P450 enzymes.
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http://dx.doi.org/10.1124/dmd.117.079574DOI Listing
July 2018

ICP-MS determination of serum aluminum in monkeys subcutaneously administered an alhydrogel-formulated drug candidate.

Bioanalysis 2017 Dec 24;9(23):1873-1881. Epub 2017 Nov 24.

Department of PK Sciences, Novartis Institutes for BioMedical Research, East Hanover, NJ 07936, USA.

Aim: To develop and validate an inductively coupled plasma-mass spectrometry method for quantitative bioanalysis of aluminum (Al) in monkey serum in support of a GLP TOX study with alhydrogel-formulated drug candidate.

Methods & Results: The method was linear over a dynamic range of 10-1000 ng/ml using a 50-μl sample volume. The intra-/inter-run precision (%CV) of the quality control sample results were ≤7.9% (CV) and the accuracy (%bias) within ±11.0% across all quality control concentrations evaluated. Other validation parameters, including stability under various conditions, extraction recovery and matrix effect, all met the acceptance criteria.

Conclusion: The validated method was successfully implemented for the quantitative analysis of Al in monkey serum to assess the systemic exposure to Al.
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http://dx.doi.org/10.4155/bio-2017-0177DOI Listing
December 2017

2017 White Paper on recent issues in bioanalysis: aren't BMV guidance/guidelines 'Scientific'? (Part 1 - LCMS: small molecules, peptides and small molecule biomarkers).

Bioanalysis 2017 Nov 17;9(22):1807-1825. Epub 2017 Nov 17.

UK MHRA, London, UK.

The 2017 11th Workshop on Recent Issues in Bioanalysis (11th WRIB) took place in Los Angeles/Universal City, California from 3 April 2017 to 7 April 2017 with participation of close to 750 professionals from pharmaceutical/biopharmaceutical companies, biotechnology companies, contract research organizations and regulatory agencies worldwide. WRIB was once again a 5-day, weeklong event - A Full Immersion Week of Bioanalysis, Biomarkers and Immunogenicity. As usual, it was specifically designed to facilitate sharing, reviewing, discussing and agreeing on approaches to address the most current issues of interest including both small and large molecule analysis involving LCMS, hybrid LBA/LCMS and ligand-binding assay (LBA) approaches. This 2017 White Paper encompasses recommendations emerging from the extensive discussions held during the workshop, and is aimed to provide the bioanalytical community with key information and practical solutions on topics and issues addressed, in an effort to enable advances in scientific excellence, improved quality and better regulatory compliance. Due to its length, the 2017 edition of this comprehensive White Paper has been divided into three parts for editorial reasons. This publication (Part 1) covers the recommendations for Small Molecules, Peptides and Small Molecule Biomarkers using LCMS. Part 2 (Biotherapeutics, Biomarkers and Immunogenicity Assays using Hybrid LBA/LCMS and Regulatory Agencies' Inputs) and Part 3 (LBA: Immunogenicity, Biomarkers and PK Assays) are published in volume 9 of Bioanalysis, issues 23 and 24 (2017), respectively.
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http://dx.doi.org/10.4155/bio-2017-4975DOI Listing
November 2017

Quantitative analysis of clofazimine (Lamprene®), an antileprosy agent, in human dried blood spots using liquid chromatography-tandem mass spectrometry.

Biomed Chromatogr 2018 Feb 20;32(2). Epub 2017 Sep 20.

Department of Pharmacokinetic Sciences, Novartis Institutes for BioMedical Research, East Hanover, New Jersey, USA.

An LC-MS/MS method was developed and validated for bioanalysis of clofazimine in human dried blood spot (DBS) samples in support of a clinical study on multidrug-resistant tuberculosis in developing countries. The validated assay dynamic range was from 10.0 to 2000 ng/mL using a 1/8 inch DBS punch. The accuracy and precision of the assay were ±11.0% (bias) and ≤13.5% (CV) for the LLOQs (10.0 ng/mL) and ±15% (bias) and ≤15% (CV) for all other QC levels. The assay was proved to be free from the possible impact owing to spot size and storage temperature (e.g. at 60°C, ≤ - 60°C). The validated assay is well suited for the intended clinical study where conventional pharmacokinetic sample collection is not feasible.
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http://dx.doi.org/10.1002/bmc.4068DOI Listing
February 2018

A continuous flocculants-free electrolytic flotation system for microalgae harvesting.

Bioresour Technol 2017 Aug 20;238:439-449. Epub 2017 Apr 20.

Center for Biorefining, and Bioproducts and Biosystems Engineering Department, University of Minnesota, 1390 Eckles Ave., Saint Paul, MN 55108, USA. Electronic address:

High harvesting cost and reusing of post-harvest water are the major challenges in commercial production of microalgae. In this work, a flocculants-free electrolytic flotation harvest process was investigated. The electrode design and materials were evaluated in terms of harvesting efficiency. Stainless steel as the cathode and carbon as the anode were selected based on the harvesting efficiency data and non-sacrificial feature for construction of a pilot scale harvesting system. In the pilot scale experiments, 23.72g/h biomass yield was achieved at the power consumption of 2.73kWh/kg. With the advantages of no chemical flocculent contamination and relatively low energy requirement, this continuous system is promising for food or feed applications.
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http://dx.doi.org/10.1016/j.biortech.2017.04.061DOI Listing
August 2017

LC-MS/MS determination of a human mAb drug candidate in rat serum using an isotopically labeled universal mAb internal standard.

J Chromatogr B Analyt Technol Biomed Life Sci 2017 Feb 4;1044-1045:166-176. Epub 2017 Jan 4.

Department of Drug Metabolism and Pharmacokinetics, Novartis Institutes for BioMedical Research, One Health Plaza, East Hanover, NJ 07936, USA.

We report the application of a liquid chromatography-tandem mass spectrometry (LC-MS/MS) bioanalytical method for the determination of a recombinant human immunoglobulin G1 (hIgG1), NVSMAb-1, in rat serum. A stable isotopically labeled universal monoclonal antibody (SILuMab), instead of stable isotopically labeled surrogate peptide, was employed as the internal standard. The internal standard was added to the sample matrix in the first step of the sample preparation process, which involved protein precipitation and pellet digestion. The digestion of the resulting pellet with trypsin was performed prior to analysis of surrogate peptides of both NVSMAb-1 and SILuMab using LC-MS/MS. Precipitation reagents (1% TCA in IPA, 75% MeOH and 14% PEG) and digestion conditions (50°C for 2h and 60°C for 0.5h) were evaluated by monitoring LC-MS/MS responses of GPS and VVS in the resulting sample extracts. Overall, the use of 1% TCA in IPA appeared to be more effective as compared to 75% methanol in protein precipitation and removal of unwanted matrix components, e.g., albumin, and more appealing than 14% PEG as it avoided additional steps that are necessary to remove PEG or reduce PEG to a negligible level. The yield (LC-MS/MS response) of GPS is less sensitive than VVS to the changes of digestion conditions (time and temperature). The results obtained using SILuMab over SIL surrogate peptide as the internal standard appeared unaffected by the suboptimal sample processing method. For the current assay, surrogate peptide GPSVFPLAPSSK (GPS) was selected as surrogate peptide over VVSVLTVLHQDWLNGK (VVS) for quantitative analysis of NVSMAb-1. The optimal chromatographic separation was achieved on a Waters Cortecs C18 (100×2.1mm, 2.7μm) column using gradient elution with a total cycle time of approximately 8min. The mobile phases were water containing 0.1% formic acid (mobile phase A) and acetonitrile containing 0.1% formic acid (mobile phase B). The current method was validated for specificity, sensitivity, matrix effect, recovery, linearity, accuracy and precision, dilution integrity, and stability. The validated assay dynamic range was 10-5000μg/mL using 20μL of rat serum. The accuracy and precision for the LLOQs (10μg/mL) were within ±6.0% bias and ≤6.5% CV, respectively. From the intra-day and inter-day assay performance evaluations, the precision of the other QC sample (30, 300, 2500 and 3750μg/mL) results were ≤6.8% CV and the accuracy within ±4.8% bias, respectively. Additional assessment of incurred sample reanalysis (ISR) was conducted to demonstrate the ruggedness and robustness of the assay method. The validated method was successfully implemented in support of a toxicity study in rats administered 30, 150 and 750mg/kg/week intravenous infusion and 150mg/kg/week subcutaneous injection of NVSMAb-1.
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http://dx.doi.org/10.1016/j.jchromb.2016.12.044DOI Listing
February 2017

Naphthoquine-induced Central Nervous System and Hepatic Vasculocentric Toxicity in the Beagle Dog.

Toxicol Pathol 2016 12 11;44(8):1128-1136. Epub 2016 Nov 11.

1 Novartis Institutes for BioMedical Research, Cambridge, Massachusetts, USA.

Naphthoquine phosphate (NP) was considered as a partner drug with a promising antimalarial drug candidate. Here we report unexpected adverse clinical signs and microscopic findings in a canine pilot toxicology study with NP. Male and female dogs were dosed daily by oral gavage with NP at 2, 10, or 50 mg/kg/day for a maximum of 14 days. NP was not tolerated at ≥10 mg/kg/day; several animals were sacrificed in moribund condition and marked neurological clinical signs were noted at 50 mg/kg/day. The main microscopic observation was central nervous system vasculocentric inflammation (mainly lymphocytes and macrophages) in the white and gray matter of various regions of the brain at ≥2 mg/kg/day and at lower incidence in the spinal cord at ≥10 mg/kg/day. Vasculocentric microscopic changes predominantly centered on the centrilobular vein were also observed in the liver at ≥2 mg/kg/day. Females were more sensitive than males with comparable NP plasma exposure. In conclusion, under the conditions of this study, the administration of NP to dogs via daily oral gavage for up to 2 weeks was not tolerated causing moribundity, marked neurological clinical signs, and vasculocentric microscopic changes in the central nervous system and the liver.
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http://dx.doi.org/10.1177/0192623316676422DOI Listing
December 2016

2016 White Paper on recent issues in bioanalysis: focus on biomarker assay validation (BAV) (Part 1 - small molecules, peptides and small molecule biomarkers by LCMS).

Bioanalysis 2016 Nov 7;8(22):2363-2378. Epub 2016 Oct 7.

Novartis, Emeryville, CA, USA.

The 2016 10 Workshop on Recent Issues in Bioanalysis (10 WRIB) took place in Orlando, Florida with participation of close to 700 professionals from pharmaceutical/biopharmaceutical companies, biotechnology companies, contract research organizations, and regulatory agencies worldwide. WRIB was once again a 5-day, weeklong event - A Full Immersion Week of Bioanalysis including Biomarkers and Immunogenicity. As usual, it was specifically designed to facilitate sharing, reviewing, discussing and agreeing on approaches to address the most current issues of interest including both small and large molecule analysis involving LCMS, hybrid LBA/LCMS, and LBA approaches, with the focus on biomarkers and immunogenicity. This 2016 White Paper encompasses recommendations emerging from the extensive discussions held during the workshop, and is aimed to provide the bioanalytical community with key information and practical solutions on topics and issues addressed, in an effort to enable advances in scientific excellence, improved quality and better regulatory compliance. This white paper is published in 3 parts due to length. This part (Part 1) discusses the recommendations for small molecules, peptides and small molecule biomarkers by LCMS. Part 2 (Hybrid LBA/LCMS and regulatory inputs from major global health authorities) and Part 3 (large molecule bioanalysis using LBA, biomarkers and immunogenicity) will be published in the Bioanalysis journal, issue 23.
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http://dx.doi.org/10.4155/bio-2016-4992DOI Listing
November 2016

Clinical Exposure Boost Predictions by Integrating Cytochrome P450 3A4-Humanized Mouse Studies With PBPK Modeling.

J Pharm Sci 2016 Apr;105(4):1398-404

Drug Metabolism & Pharmacokinetics Department, Novartis Institutes for Biomedical Research, East Hanover, New Jersey 07936. Electronic address:

NVS123 is a poorly water-soluble protease 56 inhibitor in clinical development. Data from in vitro hepatocyte studies suggested that NVS123 is mainly metabolized by CYP3A4. As a consequence of limited solubility, NVS123 therapeutic plasma exposures could not be achieved even with high doses and optimized formulations. One approach to overcome NVS123 developability issues was to increase plasma exposure by coadministrating it with an inhibitor of CYP3A4 such as ritonavir. A clinical boost effect was predicted by using physiologically based pharmacokinetic (PBPK) modeling. However, initial boost predictions lacked sufficient confidence because a key parameter, fraction of drug metabolized by CYP3A4 (fmCYP3A4), could not be estimated with accuracy on account of disconnects between in vitro and in vivo preclinical data. To accurately estimate fmCYP3A4 in human, an in vivo boost effect study was conducted using CYP3A4-humanized mouse model which showed a 33- to 56-fold exposure boost effect. Using a top-down approach, human fmCYP3A4 for NVS123 was estimated to be very high and included in the human PBPK modeling to support subsequent clinical study design. The combined use of the in vivo boost study in CYP3A4-humanized mouse model mice along with PBPK modeling accurately predicted the clinical outcome and identified a significant NVS123 exposure boost (∼42-fold increase) with ritonavir.
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http://dx.doi.org/10.1016/j.xphs.2016.01.021DOI Listing
April 2016

Differential Mobility Spectrometry Coupled with Multiple Ion Monitoring in Regulated LC-MS/MS Bioanalysis of a Therapeutic Cyclic Peptide in Human Plasma.

Anal Chem 2016 Apr 18;88(7):3655-61. Epub 2016 Mar 18.

Early Bioanalytics and Technology, Drug Metabolism and Pharmacokinetics, Novartis Institutes for BioMedical Research , One Health Plaza, East Hanover, New Jersey 07936, United States.

A differential mobility spectrometry (DMS) in combination with a multiple ion monitoring (MIM) method was developed and validated for quantitative LC-MS/MS bioanalysis of pasireotide (SOM230) in human plasma. Pasireotide, a therapeutic cyclic peptide, exhibits poor collision-induced dissociation (CID) efficiency for multiple reaction monitoring (MRM) detection. Therefore, in an effort to increase the overall sensitivity of the assay, a DMS-MIM approach was explored. By selecting the most abundant doubly charged precursor ion in both the Q1 and Q3 of the mass analyzer in MIM and combining the DMS capability to significantly reduce the high matrix/chemical background noise, this new LC-DMS-MIM method overcomes the sensitivity challenge in the typical MRM method due to poor CID fragmentation of the analyte. Human plasma was spiked with pasireotide with concentrations in the range 0.01-50 ng/mL. Weak cation-exchange solid-phase extraction was employed for sample preparation. The sample extracts were analyzed with a SCIEX QTRAP 6500 system equipped with an ESI source and DMS device. The separation voltage and compensation voltage of the DMS and other parameters of the MS system were optimized to maximize signal responses. The performance of the LC-DMS-MIM assay for quantitative analysis of pasireotide in human plasma was evaluated and compared to those obtained via LC-MRM and LC-MIM without DMS. Overall, the assay sensitivity with DMS-MIM was approximately 5-fold better than that observed in MRM or MIM without DMS. The assay was validated with accuracy (% bias) and precision (% CV) of the QC results at eight concentration levels (0.01, 0.02, 0.05, 0.15, 0.3, 1.5, 15, and 37.5 ng/mL) evaluated ranging from -4.8 to 5.0% bias and 0.7 to 8.6% CV for the intraday and interday runs. The current LC-DMS-MIM workflow can be expanded to quantitative analysis of other molecules that have poor fragmentation efficiency in CID.
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http://dx.doi.org/10.1021/acs.analchem.5b04408DOI Listing
April 2016

Quantitative analysis of factor P (Properdin) in monkey serum using immunoaffinity capturing in combination with LC-MS/MS.

Bioanalysis 2016 19;8(5):425-38. Epub 2016 Feb 19.

Department of Drug Metabolism & Pharmacokinetics, Novartis Institutes for BioMedical Research, East Hanover, NJ 07936, USA.

Aim: Factor P (Properdin), an endogenous glycoprotein, plays a key role in innate immune defense. Its quantification is important for understanding the pharmacodynamics (PD) of drug candidate(s).

Results: In the present work, an immunoaffinity capturing LC-MS/MS method has been developed and validated for the first time for the quantification of factor P in monkey serum with a dynamic range of 125 to 25,000 ng/ml using the calibration standards and QCs prepared in factor P depleted monkey serum. The intra- and inter-run precision was ≤7.2% (CV) and accuracy within ±16.8% (%Bias) across all QC levels evaluated. Results of other evaluations (e.g., stability) all met the acceptance criteria.

Conclusion: The validated method was robust and implemented in support of a preclinical PK/PD study.
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http://dx.doi.org/10.4155/bio.15.258DOI Listing
December 2016

Quantitative analysis of pasireotide (SOM230), a cyclic peptide, in monkey plasma using liquid chromatography in combination with tandem mass spectrometry.

J Chromatogr B Analyt Technol Biomed Life Sci 2016 Jan 1;1008:242-249. Epub 2015 Dec 1.

Department of Drug Metabolism and Pharmacokinetics, Novartis Institutes for BioMedical Research, One Health Plaza, East Hanover, NJ 07936, USA.

A novel liquid chromatographic method with tandem mass spectrometric detection (LC-MS/MS) for the determination of Pasireotide (SOM230) was developed and validated with a dynamic range of 0.5-250ng/ml using 50μl of monkey plasma. SOM230 and the internal standard, [M+6]SOM230, were extracted from monkey plasma via μElution SPE. The acidified sample matrix was loaded onto the preconditioned Waters SPE plate for further processing. The analyte was eluted from the SPE plate using freshly prepared elution solvent, which was followed by dilution and LC-MS/MS analysis. By eliminating a step of evaporation of the SPE eluent, instead, injecting the eluent after a simple dilution, compound loss due to non-specific binding to the 96-well materials was prevented. Furthermore, freshly prepared elution solution was found a key to optimal extraction recovery of the analyte from monkey plasma. The optimal chromatographic separation was achieved on an Atlantis dC18 (50×2.1mm, 5μm particle size) column using gradient elution with a total analysis cycle time approximately 4min per injection. The mobile phases were water containing 0.5% acetic acid and 0.05% trifluoroacetic acid (TFA) (mobile phase A) and acetonitrile containing 0.5% acetic acid and 0.05% TFA (mobile phase B). The incorporation of TFA (0.05%, v/v) and acetic acid (0.5%, v/v) into the mobile phases was accompanied by the improved chromatography and minimized carryover due to the HPLC column. The current method was validated for specificity, sensitivity, matrix effect, recovery, linearity, accuracy and precision, dilution integrity, batch size and stability. The accuracy and precision for the LLOQs (0.5ng/ml) were within ±5.6% bias and ≤7.8% CV, respectively. From the intra-day and inter-day evaluations, the precision of the other QC samples (1.5, 7.5, 75 and 190ng/ml) ranged from 2.7 to 4.9% CV and the accuracy (% bias) from -1.3 to 7.3%, respectively. Additional assessment of incurred sample reanalysis (ISR) was conducted to demonstrate the ruggedness and robustness of the assay method. The validated method was successfully implemented to support a toxicity study in monkeys administered with 5 and 30mg of SOM230 in a single intramuscular injection of a long acting release (LAR) formulation.
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http://dx.doi.org/10.1016/j.jchromb.2015.11.025DOI Listing
January 2016

2015 White Paper on recent issues in bioanalysis: focus on new technologies and biomarkers (Part 1 - small molecules by LCMS).

Bioanalysis 2015 17;7(22):2913-25. Epub 2015 Nov 17.

Merck Research Labs, West Point, PA, USA.

The 2015 9th Workshop on Recent Issues in Bioanalysis (9th WRIB) took place in Miami, Florida with participation of over 600 professionals from pharmaceutical and biopharmaceutical companies, biotechnology companies, contract research organizations and regulatory agencies worldwide. It is once again a 5-day week long event - a full immersion bioanalytical week - specifically designed to facilitate sharing, reviewing, discussing and agreeing on approaches to address the most current issues of interest in bioanalysis. The topics covered included both small and large molecules, and involved LCMS, hybrid LBA/LCMS, LBA approaches including the focus on biomarkers and immunogenicity. This 2015 White Paper encompasses recommendations that emerged from the extensive discussions held during the workshop, and is aimed to provide the bioanalytical community with key information and practical solutions on topics and issues addressed, in an effort to advance scientific excellence, improve quality and deliver better regulatory compliance. Due to its length, the 2015 edition of this comprehensive White Paper has been divided into three parts. Part 1 covers the recommendations for small molecule bioanalysis using LCMS. Part 2 (hybrid LBA/LCMS and regulatory agencies' inputs) and Part 3 (large molecule bioanalysis using LBA, biomarkers and immunogenicity) will also be published in volume 7 of Bioanalysis, issues 23 and 24, respectively.
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http://dx.doi.org/10.4155/bio.15.204DOI Listing
September 2016

Osilodrostat (LCI699), a potent 11β-hydroxylase inhibitor, administered in combination with the multireceptor-targeted somatostatin analog pasireotide: A 13-week study in rats.

Toxicol Appl Pharmacol 2015 Aug 14;286(3):224-33. Epub 2015 May 14.

Preclinical Safety, Novartis Institutes for BioMedical Research, East Hanover, NJ, USA.

The somatostatin analog pasireotide and the 11β-hydroxylase inhibitor osilodrostat (LCI699) reduce cortisol levels by distinct mechanisms of action. There exists a scientific rationale to investigate the clinical efficacy of these two agents in combination. This manuscript reports the results of a toxicology study in rats, evaluating different doses of osilodrostat and pasireotide alone and in combination. Sixty male and 60 female rats were randomized into single-sex groups to receive daily doses of pasireotide (0.3mg/kg/day, subcutaneously), osilodrostat (20mg/kg/day, orally), osilodrostat/pasireotide in combination (low dose, 1.5/0.03mg/kg/day; mid-dose, 5/0.1mg/kg/day; or high dose, 20/0.3mg/kg/day), or vehicle for 13weeks. Mean body-weight gains from baseline to Week 13 were significantly lower in the pasireotide-alone and combined-treatment groups compared to controls, and were significantly higher in female rats receiving osilodrostat monotherapy. Osilodrostat and pasireotide monotherapies were associated with significant changes in the histology and mean weights of the pituitary and adrenal glands, liver, and ovary/oviduct. Osilodrostat alone was associated with adrenocortical hypertrophy and hepatocellular hypertrophy. In combination, osilodrostat/pasireotide did not exacerbate any target organ changes and ameliorated the liver and adrenal gland changes observed with monotherapy. Cmax and AUC0-24h of osilodrostat and pasireotide increased in an approximately dose-proportional manner. In conclusion, the pasireotide and osilodrostat combination did not exacerbate changes in target organ weight or toxicity compared with either monotherapy, and had an acceptable safety profile; addition of pasireotide to the osilodrostat regimen may attenuate potential adrenal gland hyperactivation and hepatocellular hypertrophy, which are potential side effects of osilodrostat monotherapy.
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http://dx.doi.org/10.1016/j.taap.2015.05.004DOI Listing
August 2015

Evaluation of plasma microsampling for dried plasma spots (DPS) in quantitative LC-MS/MS bioanalysis using ritonavir as a model compound.

J Chromatogr B Analyt Technol Biomed Life Sci 2015 Jun 3;991:46-52. Epub 2015 Apr 3.

Department of Drug Metabolism and Pharmacokinetics, Novartis Institutes for Biomedical Research, One Health Plaza, East Hanover, NJ 07936, USA.

Quantitative bioanalysis of dried plasma spots (DPS) is not subject to the impact of hematocrit and sample non-homogeneity that are often encountered in dried blood spot (DBS) assay. In the present report, an evaluation of plasma microsampling for DPS has been conducted for the first time using ritonavir as a model compound orally administered to dogs. For this evaluation, an LC-MS/MS method was developed and validated according to the current health authorities' guidance and industry practice for the analysis of ritonavir in DPS samples. The measured ritonavir concentrations in the DPS samples prepared using SAFE-TEC devices and directly from the conventional wet plasma using standard pipette were compared with each other and against those of conventional wet plasma. Both DPS results correlated well with each other and were comparable to those of the wet plasma. Good incurred sample reanalysis results were obtained for the two sets of DPS samples and wet plasma as well. The current plasma microsampling for DPS can serve as an alternative to DPS sampling via standard pipetting and wet plasma in in vivo studies.
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http://dx.doi.org/10.1016/j.jchromb.2015.03.026DOI Listing
June 2015