The Debate is Over: Accelerator MS Provides The Route to Better Drug-Development Paradigms/Protocols
2011; Future Science Ltd; Volume: 3; Issue: 4 Linguagem: Inglês
10.4155/bio.11.9
ISSN1757-6199
Autores Tópico(s)Innovative Microfluidic and Catalytic Techniques Innovation
ResumoBioanalysisVol. 3, No. 4 ForewordFree AccessThe debate is over: accelerator MS provides the route to better drug-development paradigms/protocolsDennis A SmithDennis A SmithPharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research & Development, Sandwich, Kent, CT13 9NJ, UK. Published Online:21 Feb 2011https://doi.org/10.4155/bio.11.9AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareShare onFacebookTwitterLinkedInRedditEmail Keywords: bioavailabilitycost-savingformulationintravenousnonlinearityregistrationSome time ago, Esther Schmid and I conducted a number of analyses relating to the introduction of technology, innovation and its impact on the productivity of drug R&D [1–3]. Notwithstanding the fact that the new technology changed somewhat during the period, our conclusion was that 12–15 years was required before hard evidence of a positive change was seen. One example is high-throughput screening (HTS). The productivity of the technology was stifled for many years by target choices, compound file size and compound file quality (not drug like). Learning the lessons and adapting, it took 15 years before HTS effectively made the impact that we all recognize today, which includes marketed drugs such as maraviroc. During that time, the actual technology evolved, in terms of throughput and ability, to handle different screening configurations.The time period brings us neatly to accelerator MS (AMS). It is difficult to find evidence that AMS has made any real impact on drug R&D (it was no different for many years with HTS). Some may argue that the technique has not made an impact owing to the fact that many of the studies it has been directed at do not yield critical data or are out of sync with other R&D timelines. To conduct a microdose study you need 14C, and that puts a challenge on using AMS in what are termed Phase 0 studies. Other factors such as complexity of generating the kinetic data (chromatographic separation) also form a barrier, even if this may be imaginary. The use of AMS in drug development seems to still be in a bespoke, niche category, usually being applied when all else fails. Nevertheless, that it is available to provide solutions is becoming evident in recent literature. For instance, a conventional human absorption, distribution, metabolism and excretion study using decay counting methods for 14C detection could not be conducted due to the radiolytic instability of [14C]ixabepilone when synthesized with normal specific activity [4]. In contrast, [14C]ixabepilone was sufficiently stable at low specific activity and the use of AMS, for radioactivity detection, allowed an excretion and metabolism study to be performed [4].What changes would be needed for AMS technology to widen its impact? Is it the technique or its applications? What would propel the incredible sensitivity of AMS and its ability to allow innovative study designs and experiments to be a regular, or even the established, procedure for part of the process? That there are such study designs and experiments is given substantial reinforcement by the two accompanying papers on AMS [5,6] applied to concomitant extravascular and intravenous administration. Moving AMS to something that unarguably adds large value, is convenient to conduct (easier) and is cost neutral, is a huge step towards bringing AMS into the regular armamentarium of drug R&D. Very importantly in this move is the fact that the analytical data generated in such studies would not only advise drug R&D, it would also be used to register the drug. In most cases no other intravenous studies would be performed, meaning the data needs to be right. Performance of the analytical system, therefore, has to be more rigorous than for Phase 0 and metabolite and excretion profiling. These two papers recognize the demands placed on the analytical rigor of the technique and the authors have made an excellent job of describing the pitfalls and the solutions to the various problems to be encountered.Concomitant administration allows much better calculation and understanding of the factors that govern drug bioavailability such as fraction absorbed, gut and liver first-pass effects. Even a cross-over design lags far behind the power of concomitant administration to deconvolute the critical factors due to individual period effects. This data allows the design of better drugs, an understanding of patient variability and a platform for addressing drug–drug interactions. Moreover, any design other than concomitant is flawed where the drug displays even moderate nonlinearity in its pharmacokinetics. Concomitant solves this problem. This latter point is actually very revealing when one considers the adoption of AMS. Its use in microdose studies has always had limitations due to the possibility of nonlinear pharmacokinetics that cannot be ignored [7]. This applies, of course, independant of the analytical technique employed. In the application of concomitant, AMS is now a solution to the problem. Concomitant has been used before, using MS and stable isotopes, together with parent drug, but this does not allow the microdose and that is a critical part of why AMS concomitant is a potential winner.The above has indicated the scientific rationale for these studies, but AMS in this application is also timely. Intravenous studies for an oral drug (not marketed with an intravenous formulation) are usually performed late in Phase III partly due to the cost of producing the formulation. 14C drug is normally available, even in the most conservative companies, following a successful Phase IIA study (studies) or 'proof-of-concept'. Thus, the concomitant study can in all cases be readily performed during Phase IIB studies and available prior to commencing Phase III studies (together with the definitive human metabolism data also obtained with the 14C). This application of AMS easily moves a valuable study forward. It can do this readily because the ultra-low intravenous dose is comparatively easy to formulate compared with a normal-dose prototype or pilot-intravenous formulation. Incidentally, the cost is almost exponential to the power of the drug's Log P value (solubility being the problem). In almost all cases, for an oral drug, the savings on formulation expense more than offset any increased cost of AMS analysis.So we are 15 years into the AMS cycle and within the two articles is an application of the AMS technique that produces better quality data on a very important drug characteristic, does not require any extra synthesis and probably saves overall cost. I suggest the importance of these two articles should not be underestimated and that those interested (and that means all of us) in improving the drug R&D process should carefully read them at the first opportunity. When I say read, I mean block 2–3 h in your diary and diligently study them, not print them to file in your briefcase or today's electronic equivalent, for a quiet rainy day. AMS may be fulfilling its promise to make a real impact. AMS has the technical backing and AMS scientists are now establishing sound analytical rigor. I think AMS practioners are finding exciting applications and it is now up to industry to take the initiative.Financial & competing interests disclosureThe author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.No writing assistance was utilized in the production of this manuscript.Bibliography1 Schmid EF, Smith DA. Should scientific innovation be managed? Drug Discov. Today7(18),941–945 (2002).Crossref, Medline, Google Scholar2 Schmid EF, Smith DA. Is pharmaceutical R&D just a game of chance or can strategy make a difference? Drug Discov. Today9(1),18–26 (2004).Crossref, Medline, Google Scholar3 Schmid EF, Smith DA. Keynote review: is declining innovation in the pharmaceutical industry a myth? Drug Discov. Today10(15),1031–1039 (2005).Crossref, Medline, Google Scholar4 Comezoglu SN, Ly VT, Zhang D et al. Biotransformation profiling of [14C]ixabepilone in human plasma, urine and feces samples using accelerator mass spectrometry (AMS). Drug Metab. Pharmacokin.24(6),511–522 (2009).Crossref, Medline, CAS, Google Scholar5 Lappin G, Seymour M, Young G, Higton D, Hill HM. AMS method validation for quantitation in pharmacokinetic studies with concomitant extravascular and intravenous administration. Bioanalysis3(4),393–405 (2011).Link, CAS, Google Scholar6 Lappin G, Seymour M, Young G, Higton D, Hill HM. An AMS method to determine analyte recovery from pharmacokinetic studies with concomitant extravascular and intravenous administration. Bioanalysis3(4),407–410 (2011).Link, CAS, Google Scholar7 Smith DA, Johnson DE, Park BK. Editorial overview: use of microdosing to probe pharmacokinetics in humans – is it too much for too little? Curr. Opin. Drug Disc. Devel.6(1),39–40 (2003).CAS, Google ScholarFiguresReferencesRelatedDetailsCited ByAMS in drug development: Exploring the current utility of AMS and future opportunities for absolute bioavailability and ADME investigationsNovel Application of the Two‐Period Microtracer Approach to Determine Absolute Oral Bioavailability and Fraction Absorbed of Ertugliflozin25 March 2018 | Clinical and Translational Science, Vol. 11, No. 4Use of Accelerator Mass Spectrometry in Human Health and Molecular Toxicology11 October 2016 | Chemical Research in Toxicology, Vol. 29, No. 12Disposition and Metabolism of Darapladib, a Lipoprotein-Associated Phospholipase A2 Inhibitor, in Humans30 December 2013 | Drug Metabolism and Disposition, Vol. 42, No. 3New bioanalytical technologies and concepts: worth the fuss?Dennis A Smith13 August 2013 | Bioanalysis, Vol. 5, No. 16Selected Scientific Topics of the 11th International Isotope Symposium on the Synthesis and Applications of Isotopes and Isotopically Labeled Compounds29 July 2013 | Journal of Labelled Compounds and Radiopharmaceuticals, Vol. 56, No. 9-10Simultaneous oral therapeutic and intravenous 14 C‐microdoses to determine the absolute oral bioavailability of saxagliptin and dapagliflozin5 February 2013 | British Journal of Clinical Pharmacology, Vol. 75, No. 3Metabolism Studies In Vitro and In VivoThe best of Bioanalysis 2010Brian Booth & Howard Hill14 July 2011 | Bioanalysis, Vol. 3, No. 14 Vol. 3, No. 4 STAY CONNECTED Metrics History Published online 21 February 2011 Published in print February 2011 Information© Future Science LtdKeywordsbioavailabilitycost-savingformulationintravenousnonlinearityregistrationFinancial & competing interests disclosureThe author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.No writing assistance was utilized in the production of this manuscript.PDF download
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