Trends in microdosing and other exploratory human pharmacokinetic studies for early drug development
2010; Future Science Ltd; Volume: 2; Issue: 3 Linguagem: Inglês
10.4155/bio.10.11
ISSN1757-6199
Autores Tópico(s)Pharmaceutical Economics and Policy
ResumoBioanalysisVol. 2, No. 3 EditorialFree AccessTrends in microdosing and other exploratory human pharmacokinetic studies for early drug developmentBerend OosterhuisBerend OosterhuisPRA International, Early Development Services, PO Box 200, 9470 AE Zuidlaren, The Netherlands. Published Online:16 Mar 2010https://doi.org/10.4155/bio.10.11AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareShare onFacebookTwitterLinkedInRedditEmail During the last decade there has been considerable attention and efforts by all stakeholders to improve the science and efficiency of drug development. It was the focus of global conferences in the late 1990s and recommendations from these conferences were summarized and discussed in a publication by Lesko et al. with the input of many leading scientists [1]. In their critical path initiative, the US FDA emphasized the need for a new development toolkit to improve predictability and efficiency along the critical path from laboratory concept to commercial product [101].These and many other publications have recommended reducing the attrition rate by improving 'go/no-go' decisions with identification of the most promising drug candidates as early as possible. Problems should be detected early in order to minimize the investments in drug candidates that eventually fail. In the area of preclinical development, the availability of certain specific human in vivo data can be critical for making the right decisions. For these situations, it was already advocated in the paper by Lesko et al. that there should be the possibility of dosing drug candidates in humans before completion of the standard nonclinical and Chemistry, Manufacturing and Controls (CMC) development program, as required to support clinical Phase I studies [1]. It is obvious that short timelines for these studies and fast results are essential to avoid a delay of the ongoing nonclinical development program.In a position paper, the European Medicines Evaluation Agency (EMEA) took the first initiative to create a regulatory framework for such exploratory or 'pre-Phase I' clinical trials. A first draft for consultation was issued in 2002 and a revised final version in 2004 [2]. This guidance allowed the administration of a single 'microdose' in humans on the basis of a very limited toxicity program, including a single-dose study at one dose level in one mammalian species. A microdose was defined as a dose of 100 µg or less and at least 100-fold lower than the anticipated pharmacologically active dose (determined using animal models and/or in vitro systems). As examples of possible applications of microdose trials, the guidance mentioned 'the early characterization of a substance's pharmacokinetic (PK)/distribution properties or receptor selectivity profile using PET imaging, accelerator mass spectrometry (AMS) or other very sensitive analytical techniques.Microdosing studiesAfter the first draft of the EMEA position paper, there became a growing interest in the potential applications and advantages of pre-Phase I or 'Phase 0' microdosing studies. I am convinced that this was stimulated by pioneering providers of AMS bioanalytical services who promoted the 'microdosing concept' [3,4]. Particularly small or start-up pharmaceutical companies adopted microdosing in their early development strategy. Since most of these early studies have not been published for confidentiality reasons, it is difficult to estimate numbers of studies. As a clinical Contract Research Organization, my company has conducted over 15 Phase 0 microdosing studies for over ten sponsors in the last 6 years. These were studies in which one or more early drug-candidate compounds were administered in humans, often in a two-period crossover design, with intravenous dosing in one period and oral dosing or other route of administration in the other. The 100 µg or less doses contained tracer amounts (50–500 nanoCurie) of 14C-radiolabeled drug compound, to allow AMS bioanalysis. In most studies, multiple compounds (up to five) were compared with one panel of four to six subjects per compound. In these studies, the objective was to select one, from multiple candidates, with the most appropriate PK characteristics. In two studies with topical administration, the objective was to rule out or estimate systemic exposure. In two other studies, the effect of CYP3A4 inhibition on the PK of a drug candidate was tested.Most of these studies effectively produced results to support decision making. Some have been published in the literature [5] or reported in scientific meetings [6].In the meantime, controversy remained among clinical pharmacologists about the value of PK data derived from a 100 µg or less dose in a few subjects to predict PK at pharmacological doses. There was concern that dose- and concentration-dependent mechanisms in drug metabolism and transport/distribution could make the extrapolation from microdose to pharmacological dose unreliable [7,8].This was the rationale for the initiation of two cooperative studies on existing drugs to compare in healthy volunteers: their PK profile after a microdose and after a pharmacological dose and/or their PK data in the literature [9,102]. My company participated as one of the partners in these studies, taking care of the clinical conduct and GMP-manufacturing of the microdose formulations. The drugs selected were all known to be problematic in terms of human PK prediction from animal and in vitro PK data for different reasons. In total, 12 drugs were evaluated in these studies. For two compounds, the results were inconclusive due to technical problems. For seven out of ten 'evaluable' compounds, the microdose results predicted the pharmacological dose results within a factor of two for all relevant PK parameters. For four of the compounds, there was a remarkable similarity between the dose-corrected PK parameters for microdose and pharmacological dose within-study. However, for three compounds one or more, PK parameters were predicted with more than a twofold error, which was apparently due to saturable/concentration-dependent mechanisms in their disposition. In general, it was concluded from these studies that the data obtained after microdosing would have been useful in the selection of drug candidates for further development (or dropped from the development pipeline). By contrast, three out of ten compounds with erroneous predictions suggest that the concerns about microdosing are not groundless.Moving to higher doses in exploratory human PK studiesIn addition to theoretical concerns regarding the extrapolation of PK data based on a 100-µg dose, microdosing studies have some practical disadvantages. First, it is the need to use AMS for the assay of PK samples. AMS assays are relatively expensive and our experience shows that they have taken more time than expected for several studies. Subsequently, this is the need for 14C-labeled compound of the drug candidate in the microdose. In practice, this is a complicating factor, which causes delay and increases the costs of a microdose study.Owing to the issues above, I expect that that the focus will shift from microdose to low-dose exploratory human PK studies. Instead of a 100-µg dose, the dose in such studies should be more close to the eventual pharmacological dose. Typically, the aim is to be in the lower part of the dose range in Phase I. As a primary advantage, this could make the extrapolation of the PK results more reliable. Even the assessment of some pharmacodynamics may become an option. Other advantages are that no radiolabeled compound is required since bioanalysis by sensitive LC–MS/MS becomes an option [10]. The time and costs spent otherwise for manufacturing of radiolabeled compounds in a microdose study can now be spent on the set-up and validation of a highly sensitive LC–MS/MS method. After the clinical stage, the bioanalysis of the study samples will be faster and cheaper.At the same time, there remains an important role for AMS in combination with tracer doses of 14C-labeled drug compound. We are seeing a trend that these are applied during early Phase I studies rather than Phase 0 studies. This appears to provide valuable additional information, such as absolute bioavailability and early data on metabolism in humans.Toxicity studies to support exploratory low-dose human PK studiesThe shift from microdosing to low-pharmacological dose exploratory studies is facilitated by developments in the regulatory field. In 2006, the FDA issued their final Guidance for Industry 'Exploratory IND Studies' [11]. In this guidance, the FDA extends the option of microdosing with exploratory studies at higher single doses and even multiple doses.Recently, a second revision of the International Conference on Harmonization (ICH) M3 guideline (ICH M3 R2 step 4) has been enforced by the EMEA (and will be adopted by the FDA) [12], which supersedes the EMEA position paper on microdosing [2]. The ICH M3(R2) provides guidance for several approaches in exploratory clinical trials. Five different approaches are described, with recommendations for the supporting nonclinical studies. The optimal scenario for an exploratory low-dose human PK study could be an intermediate between approach 1 and approach 3, according to the ICH M3(R2). The supporting nonclinical program will require slightly more drug substance than the standard program to support a microdose. However, it will not require more time.Manufacturing of medication for early exploratory studiesAn aspect that has received little attention in the literature is how to deal with the pharmaceutical quality and good manufacturing practice of the investigational product in these early exploratory studies when CMC development is also in an early stage. We have the experience that small start-up or pioneering companies are often keen to use any flexibility that is allowed by the guidelines. However, in big pharmaceutical companies, there tends to be reluctance to deviate from established internal standard procedures and formal GMP routines. This appears to increase the involved resources and causes unacceptable timelines. As a consequence, the manufacturing of the investigational medicinal product has become a major hurdle for the viability of early exploratory studies by many of these companies. We propose that the manufacturing of the drug product for early exploratory studies should occur in a flexible small-scale unit at the site of the clinical study. Facilities and procedures should comply with basic GMP principles. Rational specifications, proper QC-checks and short timelines for manufacturing are key success factors for these studies.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 Lesko LJ, Rowland M, Peck CC, Blaschke TF. 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Microdosing in early clinical development: a case study with human renin inhibitors. Presented at: Exploratory Clinical Development Congress. Earls Court Conference Centre, London, UK, 21–22 February 2007.Google Scholar7 Bertino JS Jr, Greenberg HE, Reed MD. American College of Clinical Pharmacology position statement on the use of microdosing in the drug development process. J. Clin. Pharmacol.47,418–422 (2007).Crossref, Medline, CAS, Google Scholar8 Rowland M. Commentary on ACCP position statement on the use of microdosing in the drug development process. J. Clin. Pharmacol.47,1595–1596; author reply 1597–1598 (2007).Crossref, Medline, Google Scholar9 Lappin G, Kuhnz W, Jochemsen R et al. Use of microdosing to predict pharmacokinetics at the therapeutic dose: experience with 5 drugs. Clin. Pharmacol. Ther.80,203–215 (2006).Crossref, Medline, CAS, Google Scholar10 Lappin G, Wagner CC, Langer O, Van de Merbel N. New ultrasensitive detection technologies and techniques for use in microdosing studies. Bioanalysis1(2),357–366 (2009).Link, CAS, Google Scholar11 Guidance for Industry, Investigators, and Reviewers. Exploratory IND Studies. FDA, CDER, January 2006.Google Scholar12 ICH Topic M3 (R2) Non-Clinical Safety Studies for the Conduct of Human Clinical Trials and Marketing Authorization for Pharmaceuticals: CPMP/ICH/286/95. June 2009.Google Scholar101 US FDA: Innovation or stagnation? Challenge and opportunity on the critical path to new medical products. FDA, critical path report. March 2004 www.fda.gov/ScienceResearch/SpecialTopics/CriticalPathInitiative/CriticalPathOpportunitiesReports/ucm077262.htmGoogle Scholar102 European Microdosing AMS Partnership Programme www.eumapp.com/pdfs/EUMAPP%20SUMMARY.pdfGoogle ScholarFiguresReferencesRelatedDetailsCited ByDetermination of [ 11 C]Rifampin Pharmacokinetics within Mycobacterium tuberculosis-Infected Mice by Using Dynamic Positron Emission Tomography BioimagingAntimicrobial Agents and Chemotherapy, Vol. 59, No. 9Alternative Models in Drug Discovery and Development Part II: In Vivo Nonmammalian and Exploratory/Experimental Human Models11 August 2014Selected 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. 9-10Microdosing and drug development: past, present and future4 April 2013 | Expert Opinion on Drug Metabolism & Toxicology, Vol. 9, No. 7Challenges in sexual medicine10 July 2012 | Nature Reviews Urology, Vol. 9, No. 9Predicting Drug Candidate Victims of Drug-Drug Interactions, using MicrodosingClinical Pharmacokinetics, Vol. 51, No. 4Alternative (non-animal) methods for cosmetics testing: current status and future prospects—20101 May 2011 | Archives of Toxicology, Vol. 85, No. 5 Vol. 2, No. 3 Follow us on social media for the latest updates Metrics History Published online 16 March 2010 Published in print March 2010 Information© Future Science LtdFinancial & 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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