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A Review on Liquid Chromatography-Tandem Mass Spectrometry Methods for Rapid Quantification of Oncology Drugs

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A Review on Liquid Chromatography-Tandem Mass Spectrometry Methods for Rapid Quantification of Oncology Drugs pharmaceutics Review A Review on Liquid Chromatography-Tandem Mass Spectrometry Methods for Rapid Quantification of Oncology Drugs Andrea Li-Ann Wong 1,2,†, Xiaoqiang Xiang 3,†, Pei Shi Ong 4, Ee Qin Ying Mitchell 4, Nicholas Syn 1,2, Ian Wee 1,2, Alan Prem Kumar 1,5 , Wei Peng Yong 1,2, Gautam Sethi 5, Boon Cher Goh 1,2,5,*, Paul Chi-Lui Ho 4,* and Lingzhi Wang 1,5,* 1 Cancer Science Institute of Singapore, National University of Singapore, Singapore 117599, Singapore; [email protected] (A.L.-A.W.); [email protected] (N.S.); [email protected] (I.W.); [email protected] (A.P.K.); [email protected] (W.P.Y.) 2 Department of Haematology-Oncology, National University Health System, Singapore 119228, Singapore 3 School of Pharmacy, Fudan University, Shanghai 201203, China; [email protected] 4 Department of Pharmacy, National University of Singapore, Singapore 117543, Singapore; [email protected] (P.S.O.); [email protected] (E.Q.Y.M.) 5 Department of Pharmacology, Yong Loo Lin School of Medicine, Singapore 117597, Singapore; [email protected] * Correspondence: [email protected] (B.C.G.); [email protected] (P.C.-L.H.); [email protected] (L.W.); Tel.: +65-6772-4140 (B.C.G.); +65-6516-2651 (P.C.-L.H.); +65-6516-8925 (L.W.); Fax: +65-68739664 (B.C.G. & L.W.); +65-6777-5545 (P.C.-L.H.) † Equal contribution. Received: 15 October 2018; Accepted: 5 November 2018; Published: 8 November 2018 Abstract: In the last decade, the tremendous improvement in the sensitivity and also affordability of liquid chromatography-tandem mass spectrometry (LC-MS/MS) has revolutionized its application in pharmaceutical analysis, resulting in widespread employment of LC-MS/MS in determining pharmaceutical compounds, including anticancer drugs in pharmaceutical research and also industries. Currently, LC-MS/MS has been widely used to quantify small molecule oncology drugs in various biological matrices to support preclinical and clinical pharmacokinetic studies in R&D of oncology drugs. This mini-review article will describe the state-of-the-art LC-MS/MS and its application in rapid quantification of small molecule anticancer drugs. In addition, efforts have also been made in this review to address several key aspects in the development of rapid LC-MS/MS methods, including sample preparation, chromatographic separation, and matrix effect evaluation. Keywords: LC-MS/MS; rapid; quantification; oncology drugs 1. Introduction Cancer has a major impact on global health as it is the second leading cause of death. According to the World Cancer Report 2014, the number of new cancer cases is expected to rise by about 70% over the next two decades [1]. This is due to the rapidly ageing population, unhealthy lifestyles, and environmental pollutants, which could consist of carcinogens that can be present in the air, water, and soil, as well as in food as additives or contaminants. Early diagnosis of cancer allows timely treatment of the disease. Unfortunately, the early detection of cancer is still in its infancy as the progress in developing improved early diagnostics and screening tests has been inadequate. For instance, close to 70% of patients with lung cancer present with locally advanced or metastatic disease at the time of diagnosis. Therefore, surgical resection, the single most consistent and successful Pharmaceutics 2018, 10, 221; doi:10.3390/pharmaceutics10040221 www.mdpi.com/journal/pharmaceutics Pharmaceutics 2018, 10, x 2 of 19 Pharmaceutics 2018, 10, 221 2 of 20 disease at the time of diagnosis. Therefore, surgical resection, the single most consistent and successful option for cure, cannot be performed [2]. This thereby makes chemotherapy an important treatmentoption for cure,option cannot against be performedcancer. Anticancer [2]. This therebydrugs makesare characterized chemotherapy by ana importantnarrow therapeutic treatment window.option against Hence, cancer. it is important Anticancer to drugs understand are characterized and manage by a the narrow inter-individual therapeutic window. variability Hence, of drug it is exposureimportant through to understand genotyping/phenotyping and manage the inter-individualand therapeutic drug variability monitoring of drug (TDM) exposure of anticancer through drugsgenotyping/phenotyping in the clinical setting. and therapeutic In the pharmaceutical drug monitoring industry, (TDM) ofthe anticancer current drugschallenges in the clinicalin the developmentsetting. In the of pharmaceuticalanticancer drugs industry, include thethe currentsignificant challenges time and in cost the required development for the of preclinical anticancer anddrugs clinical include testing the significant of the new time chemical and cost entities required (NCEs), for the and preclinical the low and success clinical rates. testing To ofovercome the new thesechemical obstacles, entities the (NCEs), pharmaceutical and the low industry success has rates. been To increasing overcome theseits effort obstacles, to improve the pharmaceutical the efficiency inindustry the processes has been of drug increasing discovery its effort and development. to improve the This efficiency is in line in with the processesthe objective of drugof reducing discovery the attritionand development. rate of NCEs This at is later in line stages with of the the objective anticancer ofreducing drug development the attrition pipeline, rate of NCEsespecially at later in clinicalstages of trials the anticanceras by that stage drug developmenta large portion pipeline, of the cost especially of developing in clinical an trialsoncology as by drug that stagewould a largehave beenportion incurred. of the cost According of developing to a review an oncology article, drug two would major haveunderlying been incurred. reasons According accounting to for a review drug attritionarticle, two were major identified underlying [3]. reasonsThe first accounting one is due for to drug poor attrition efficacy, were which identified can be [3 ].overcome The first oneby developingis due to poor more efficacy, predictive which animal can be overcomemodels in by the developing preclinical more phase. predictive The second animal crucial models factor in the is owingpreclinical to poor phase. pharmacokinetics The second crucial (PK). factor To overcome is owing tothe poor latter pharmacokinetics hurdle, a high throughput (PK). To overcome preclinical the screeninglatter hurdle, PK aapproach high throughput should be preclinical developed screening and vali PKdated. approach However, should the be success developed of PK and analysis validated. is highlyHowever, dependent the success on the of PKavailability analysis of is rapid highly and dependent sensitiveon bioanalytical the availability assays of for rapid quantification and sensitive of drugsbioanalytical in biological assays samples. for quantification Therefore, of drugsrapid inand biological sensitive samples. quantification Therefore, of anticancer rapid and sensitivedrugs in variousquantification biological of anticancer matrices drugsis urgently in various needed biological to discover matrices novel is urgently and effective needed chemotherapeutic to discover novel agentsand effective against chemotherapeutic various cancers. Liquid agents againstchromatography-tandem various cancers. Liquidmass spectrometry chromatography-tandem (LC-MS/MS) offersmass spectrometrysuperior specificity (LC-MS/MS) and offerssensitivity superior for specificitycompounds and without sensitivity natural for compounds chromophores without or fluorophores.natural chromophores Hence, this or fluorophores. highly sensitive Hence, and this specific highly sensitiveplatform andhas specificbeen widely platform applied has been in widelyinvestigating applied pharmacokinetic in investigating pharmacokineticproperties of novel properties anticancer of novel drugs anticancer in their drugs R&D in in their preclinical R&D in studiespreclinical as well studies as asin wellclinical as intrials. clinical The trials. workflow The workflow of LC-MS/MS of LC-MS/MS proposed proposed for bioanalytical for bioanalytical method developmentmethod development is shown is shownin Figure in Figure 1. The1. Thesuccess success for fordeveloping developing rapid rapid and and sensitive sensitive analyticalanalytical methods isis dependentdependent on on appropriate appropriate sample sample preparation, preparation, fast chromatographicfast chromatographic separation separation to achieve to achievesymmetrical symmetrical peaks, and peaks, efficient and efficient ionization. ionization. The purpose of of this this review review is is to to summarize summarize the the rapid rapid LC-MS/MS LC-MS/MS methods methods for for quantification quantification of oncologyof oncology drugs drugs or orpotential potential anticancer anticancer compounds compounds published published in in PubMed PubMed and and Web Web of of Science databases. In In addition, addition, important important considerations considerations regarding regarding several several crucial crucial aspects in developing rapid LC-MS/MS methods, methods, such such as as sample sample preparation, chromatographic separation, matrix effect evaluation, and internal standard selection will be discussed. Figure 1.1.Pipeline Pipeline for conductingfor conducting bioanalysis bioanalysis using liquid using chromatography-tandem liquid chromatography-tandem mass spectrometry. mass 2. Methodspectrometry. of Literature Search 2. MethodThe literature of Literature search Search was conducted using the PubMed
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