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LETTER TO THE EDITOR |
Bertino Consulting Schenectady, New York and Associate Professor of Pharmacology, College of Physicians and Surgeons, Columbia University, New York, New York
Mount Sinai School of Medicine, New York
Department of Pediatrics, Akron Children's Hospital, Akron, Ohio
Address for correspondence: Joseph S. Bertino Jr., PharmD, FCP, Bertino Consulting, 3078 New Williamsburg Drive, Schenectady, NY 12303; e-mail: sbertino{at}ix.netcom.com.
Dr Rowland has raised a number of interesting issues in his comments to the American College of Clinical Pharmacology (ACCP) position statement on microdosing.1 We thank him for his thoughtful comments and suggest that this type of intellectual debate contributes positively to moving the drug development paradigm forward, particularly as it relates to the relatively new tool of microdosing. We fully agree with Rowland that this tool has potential that will only be fully appreciated after substantially more critical assessment and validation. However, based on our assessment of published experiences with microdosing methodologies, our enthusiasm for the broader application of this tool is tempered, at least at present, until more published data are available.
The CREAM (Consortium for Resourcing and Evaluating AMS [Accelerator Mass Spectrometry] Microdosing) trial represents the most comprehensive published data evaluating the strengths and limitations of microdosing methodologies in drug development to date. However, the focus of the ACCP position statement embraces the larger spectrum of drug development beyond the 5 probe compounds described in this publication.2 We, like Rowland, encourage individuals involved in drug development to read this communication. Rowland accurately notes that a central tenant of microdosing "is not one of robustly demonstrating strict pharmacokinetic linearity," and it was not our intention to suggest anything different. Microdosing methodologies, like many other strategies in the new drug development toolbox, provide a finite snapshot of specific aspects of drug disposition. Using published data, we simply raised potential concerns that are very likely to arise sometime during the study of any new drug based on the compound's integrated pharmacokinetic-pharmacodynamic-pharmacogenomic profiles. Rowland also states that the suggestion of applying narrower limits for the prediction of phase I dosing of compounds with narrow therapeutic ranges is "laudable [but] it is perhaps unrealistic given the uncertainty in the human safety profile, activity of metabolites, and other factors." These comments and others regarding phase I dosing do not accurately reflect the stated opinion outlined in our commentary. The statements presented regarding variability were solely directed at pharmacokinetic findings and independent of drug safety. Like Rowland, we would all agree that study subject/patient safety is of utmost concern in all phases of the drug development process and that whatever safeguards that might or are required must be ensured. The recently chronicled tragedies surrounding the study of TGN14123-5 serve to remind us all of the risks associated with drug administration to humans, independent of study design, and the responsibilities each of us as clinical investigators have for study subject protection.
The specific issues Rowland raises regarding our comments on ZK253 bioavailability and sampling times employed in the CREAM study2 are, in our opinion, an oversimplification of the scope of variability and importance of these 2 processes to interphase drug development decision making. We agree with Rowland—that is, a "commonly held view, widely adopted when using allometric scaling of animal to human pharmacokinetics, is that prediction within 2-fold of the mean observed in phase I study is acceptable, which was certainly so for the diazepam microdose data." This is a laudable goal but, even with the best of allometric scaling, can oftentimes be elusive, particularly for drugs that undergo extensive metabolism by polymorphically expressed enzymes (eg, CYP2D6). Furthermore, our comments regarding study "n" are mischaracterized as we completely agree with Dr Rowland regarding the desirability, but the limitations, of small sample sizes and the continuous need for evidence-driven balance between data quality, broad applicability, safety, and cost efficiency. Nevertheless, depending on the compound, intrasubject variability may be much greater than eluded to by Rowland,6 recognizing that the focus here is on new, presumably unknown compounds. This would be of paramount importance for compounds representing a new class that might markedly limit the utility of "a substantial body of human therapeutic data [that] usually already exists to serve as reference." Obviously, when such data are available, their value to study design and sample size projections are invaluable, as demonstrated clearly by the CREAM trial—our comments were focused on the situations where such human data are not available and anticipating the possibility where the animal data may not accurately reflect what is observed in the human.
We further agree with Rowland that "pharmacokinetics reflects rather than perturbs the state of an individual." However, circumstances do or can arise where a drug undergoes metabolism by a drug-metabolizing enzyme that exhibits polymorphism (eg, CYP2D6), where a poor metabolizer with no appreciable enzyme activity can yet have alternative pathways that can eliminate the drug.7 Although these alternative pathways are generally not as efficient as the primary pathways, they nevertheless do result in drug clearance from the body.7 Our point in the ACCP position paper is that with microdoses (ie, 1/100th of the "therapeutic dose"), metabolism by these alternative pathways (even in poor metabolizers) may be sufficient to eliminate the drug in a manner similar to the rate observed in extensive metabolizers at therapeutic doses. This would result in "false" data being generated in poor metabolizers, which, when applied using therapeutic dosages in these individuals, could result in significant toxicity in phase I studies. It would be of use to the scientific community to examine this.
Dr Rowland appropriately emphasizes that microdosing is only one tool for drug development, with which the position paper fully embraces. The questions Rowland outlines in his letter that remain to be determined with microdosing methodologies are valid and will only be adequately addressed after further use of microdosing methodology, coupled with public presentation and publication of the findings for the entire scientific community to evaluate in an open fashion. It is our understanding (personal communications) that many drug discovery programs and drug development sponsors have incorporated microdosing methods in their drug development studies, but the data remain "buried" in the "sponsors'" archives and unavailable for peer review and critique. To fully appreciate the strengths and limitations of microdosing or any other bold new study design to be implemented in the new drug development paradigm, we appeal to those investigators and their corporations along with proponents of microdosing to publish their findings. Only with the open sharing of such experiences will we reap the benefits of new technologies as we move new drug development forward.
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ACKNOWLEDGEMENTS |
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TOPACKNOWLEDGEMENTSREFERENCES |
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1. Bertino JS, Greenberg HE, Reed MD. American College of Clinical Pharmacology position statement on the use of microdosing in the drug development process. J Clin Pharmacol. 2007; 47: 418-422.
2. Lappin G, Kuhnz H, Jochemsen R, et al. Use of microdosing to predict pharmacokinetics at the therapeutic dose: Experience with five drugs. Clin Pharmacol Ther. 2006;80: 203-217.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
3. Snell NJC. Human volunteer studies—safety considerations in an era of highly active biological agents: lessons from the Tegenero tragedy. Int J Pharm Med. 2006;20: 293-296.[CrossRef]
4. Kenter MJH, Cohen AF. Establishing risk of human experimentation with drugs: lessons from TGN1412. Lancet. 2006;368: 1387-1991.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
5. Wood AJJ, Darbyshire J. Injury to research volunteers: the clinical-research nightmare. N Engl J Med. 2006;354: 1869-1871.
6. Kashuba ADM, Nafziger AN, Kearns GL, et al. Quantitation of long-term intraindividual variability and the influence of menstrual cycle phase on CYP2D6 activity as measured by dextromethorphan phenotyping. Pharmacogenetics. 1998;8: 403-410.[Web of Science][Medline] [Order article via Infotrieve]
7. Eap CB, Lessard E, Baumann P, et al. Role of CYP2D6 in the stereoselective disposition of venlafaxine in humans. Pharmacogenetics. 2003;13: 39-47.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
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