Improved early clinical development through human microdosing studies

Wilding, Ian R.; Bell, James A.

doi:10.1016/s1359-6446(05)03509-9

Cited by 39 publications

(31 citation statements)

References 14 publications

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“…Microdosing has the potential for estimating human pharmacokinetics at therapeutic dose levels with much lower preclinical safety and compound requirements [ICH (2000) Garner, 2005;Wilding and Bell, 2005]. Microdosing studies performed before phase I have the potential to reduce the attrition of drugs because of inadequate pharmacokinetic properties in humans and reduce the cost and time to reach this decision point.…”

Section: Introductionmentioning

confidence: 99%

“…Application of this approach is also described for an investigational compound, MLNX, in which the pharmacokinetics in rats were determined to be nonlinear, suggesting that MLNX pharmacokinetics at microdoses in humans also might not reflect those at the therapeutic doses. These preclinical studies demonstrate the potential applicability of using traditional LC-MS/MS for microdose pharmacokinetic assessment in humans.Microdosing has the potential for estimating human pharmacokinetics at therapeutic dose levels with much lower preclinical safety and compound requirements [ICH (2000) Garner, 2005;Wilding and Bell, 2005]. Microdosing studies performed before phase I have the potential to reduce the attrition of drugs because of inadequate pharmacokinetic properties in humans and reduce the cost and time to reach this decision point.…”

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confidence: 99%

“…CPMP/SWP2599/02/Rev 1. http://www.emea.eu.int/pdfs/ human/swp/259902en.pdf; FDA Draft Guidance #6384dft (2005) on Exploratory IND Studies http://www.fda.gov/cder/guidance/6384dft. doc; Garner, 2005;Wilding and Bell, 2005]. Microdosing studies performed before phase I have the potential to reduce the attrition of drugs because of inadequate pharmacokinetic properties in humans and reduce the cost and time to reach this decision point.…”

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Evaluation of Microdosing to Assess Pharmacokinetic Linearity in Rats Using Liquid Chromatography-Tandem Mass Spectrometry

Balani

Nagaraja²,

Qian³

et al. 2005

Drug Metab Dispos

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ABSTRACT:The microdosing strategy allows for early assessment of human pharmacokinetics of new chemical entities using more limited safety assessment requirements than those requisite for a conventional phase I program. The current choice for evaluating microdosing is accelerator mass spectrometry (AMS) due to its ultrasensitivity for detecting radiotracers. However, the AMS technique is still expensive to be used routinely and requires the preparation of radiolabeled compounds. This report describes a feasibility study with conventional liquid chromatography-tandem mass spectrometry (LC-MS/MS) technology for oral microdosing assessment in rats, a commonly used preclinical species. The nonlabeled drugs fluconazole and tolbutamide were studied because of their similar pharmacokinetics characteristics in rats and humans. We demonstrate that pharmacokinetics can be readily characterized by LC-MS/MS at a microdose of 1 g/kg for these molecules in rats, and, hence, LC-MS/MS should be adequate in human microdosing studies. The studies also exhibit linearity in exposure between the microdose and >1000-fold higher doses in rats for these drugs, which are known to show a linear doseexposure relationship in the clinic, further substantiating the potential utility of LC-MS/MS in defining pharmacokinetics from the microdose of drugs. These data should increase confidence in the use of LC-MS/MS in microdose pharmacokinetics studies of new chemical entities in humans. Application of this approach is also described for an investigational compound, MLNX, in which the pharmacokinetics in rats were determined to be nonlinear, suggesting that MLNX pharmacokinetics at microdoses in humans also might not reflect those at the therapeutic doses. These preclinical studies demonstrate the potential applicability of using traditional LC-MS/MS for microdose pharmacokinetic assessment in humans.Microdosing has the potential for estimating human pharmacokinetics at therapeutic dose levels with much lower preclinical safety and compound requirements [ICH (2000) Garner, 2005;Wilding and Bell, 2005]. Microdosing studies performed before phase I have the potential to reduce the attrition of drugs because of inadequate pharmacokinetic properties in humans and reduce the cost and time to reach this decision point. Currently, accelerator mass spectrometry (AMS) is the technology of choice for microdosing assessments, allowing ultrasensitive, femto or attomol drug level measurements. There is a growing literature on the use of AMS in preclinical and clinical research (Kaye et al., 1997;Young et al., 2001;Garner et al., 2002;Liberman et al., 2004;Sandhu et al., 2004;Choi et al., 2005;Sarapa et al., 2005). The extremely low amounts of radioactivity required for AMS permits human studies to be conducted without extensive regulatory approvals for radiation safety (Barker and Garner, 1999 DMD 34:384-388, 2006 Printed in U.S.A.Vol. 34, No. 3 Copyright © 2006 by The American Society for Pharmacology and Experimental Therapeutics 7195/3085572 384at ASPE...

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Section: Introductionmentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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Evaluation of Microdosing to Assess Pharmacokinetic Linearity in Rats Using Liquid Chromatography-Tandem Mass Spectrometry

Balani

Nagaraja²,

Qian³

et al. 2005

Drug Metab Dispos

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“…The ADME data from microdose studies can be fed into in silico PK models to obtain a much better estimate of the probable pharmacological dose in future efficacy studies 5 .…”

Section: Issn: 0975-8232mentioning

confidence: 99%

“…Its management requires clear strategies and decision making processes to tackle the trade-offs in cost, time, product value and success probability that occur within individual projects and across product portfolios. The importance of this endeavour is underlined by a stark reality that 75% of the cost of drug development is on failures concentrated in early stages 3 and reducing the cost of this failure-either by falling the candidates sooner or by improving the overall probability of success is the most powerful solution for improving R & D productivity 4,5 .…”

Section: Introductionmentioning

confidence: 99%

Untitled

2011

IJPSR

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New drugs are a great need for clinical conditions but unfortunately development costs are rising and number of drugs receiving marketing approval has fallen. Microdosing is a new experimental approach that offers a faster and potentially less expensive approach for obtaining human in vivo pharmacokinetic (PK) data in early stages of drug development. The concept of microdosing involves the use of extremely low non-pharmacologically active doses of drug candidates to define their PK profile in human subjects, using highly sensitive analytical techniques such as Accelerator mass spectrometry (AMS), Positron emission tomography (PET) and Liquid chromatography-mass spectrometry-mass spectrometry (LC/MS/MS). In this review we have discussed various aspects of microdosing such as regulatory requirements, methodology, validation, experimental proofs and future aspects. In conclusion, progress on three fronts, namely analytical, regulatory and understanding the role of PK in drug development has bought pharmaceutical industry to a position where microdosing can be considered as a possible first step in clinical investigations and eventually all first in human studies will commence with a phase 0 study.

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Interrelationship between Pharmacokinetics and Metabolism

Paxton

2010

Pharmaceutical Sciences Encyclopedia

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In drug development, approximately 40% of all new chemical entities (NCEs) fail to become clinically successful drugs due to undesirable pharmacokinetic properties. A knowledge of the capacity for the metabolism of an NCE and an understanding of the human metabolism pathways and the enzymes involved have now become key components in the selection of compounds for clinical development. This article examines the relationship between metabolism and the resulting pharmacokinetic profile of a drug, and reviews the major factors that may have an impact on a drug's metabolism and may have a detrimental effect on its pharmacokinetics and clinical use.

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Improved early clinical development through human microdosing studies

Cited by 39 publications

References 14 publications

Evaluation of Microdosing to Assess Pharmacokinetic Linearity in Rats Using Liquid Chromatography-Tandem Mass Spectrometry

Evaluation of Microdosing to Assess Pharmacokinetic Linearity in Rats Using Liquid Chromatography-Tandem Mass Spectrometry

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Interrelationship between Pharmacokinetics and Metabolism

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