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Clinical Relevance of Liquid Chromatography Tandem Mass Spectrometry as an Analytical Method in Microdose Clinical Studies

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ABSTRACT

Purpose

To investigate the potency of LC-MS/MS by means of sensitivity and the applicability for cassette dosing in microdose clinical trials.

Methods

Thirty one top-selling 31 drugs were spiked to human plasma, extracted, and analyzed by LC–MS/MS.

Results

The lower limits of quantification for each drug varied from 0.08 to 50 pg/mL, and were lower than one eighth of the assumed maximum plasma concentration at microdose in all drugs except for losartan, indicating the high performance in acquisition of full pharmacokinetic profiles at microdose. We also succeeded in simultaneous analysis of multiple compounds, assuming a situation of cassette dosing in which multiple drug candidates would be administrated simultaneously.

Conclusions

Together with the features of LC–MS/MS, such as immediate verification, the utilization of non-radiolabeled drugs and no special facilities, we suppose that LC–MS/MS analysis would be widely applicable in conducting microdose clinical studies.

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Abbreviations

AMS:

accelerator mass spectrometry

CmaxClin :

Cmax in clinical PK study

CmaxMD :

Cmax in microdose study

CV:

coefficient of variation

DoseClin :

dose in clinical PK study

DoseMD :

dose in microdose study

EMEA:

European Agency for the Evaluation of Medicinal Products

EUMAPP:

European Union Microdose AMS Partnership Programme

FDA:

Food and Drug Administration

HILIC:

hydrophilic interaction chromatography

IS:

internal standard

LC–MS/MS:

liquid chromatography-tandem mass spectrometry

LLE:

liquid-liquid extraction

LLOQ:

lower limit of quantification

MHLW:

Ministry of Health Labour and Welfare

MRM:

multiple reaction monitoring

ODS:

octadecylsilyl

PET:

positron emission tomography

PK:

pharmacokinetic

QC:

quality control

RE:

relative error

SPE:

solid-phase extraction

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ACKNOWLEDGMENTS

Naoe Yamane is an employee of JCL Bioassay Corporation, Hyogo, Japan. We thank Drs. M. Shibasaki, M. Kanai, and K. Yamatsugu of the Graduate School of Pharmaceutical Sciences at the University of Tokyo, Japan, for donating the gift of oseltamivir phosphate. We also thank to Dr. T. Tanimoto of the School of Pharmaceutical Sciences, Mukogawa Women’s University, Japan, for sharing the reagents with us, and T. Hakui and M. Nishimura of GL Science Inc. for technical support of SPE methods. This work was performed as part of “Innovative Strategies for Drug Development Using Microdosing Clinical Studies,” financed by the New Energy and Industrial Technology Development Organization (NEDO). A part of this work has been presented at the 23rd JSSX (The Japanese Society for the Study of Xenobiotics) Annual Meeting “Study on practical application for liquid chromatography/tandem mass spectrometry for determination of drug concentration in human plasma in microdose study.”

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Authors and Affiliations

  1. Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo, Bunkyo-ku, 113–0033, Japan

    Naoe Yamane, Makiko Kusama, Kazuya Maeda & Yuichi Sugiyama

  2. Sekisui Medical Co., Ltd., Muramatsu, Tokai, 319–1182, Japan

    Zenzaburo Tozuka

  3. Yokohama College of Pharmacy, Yokohama, Kanagawa, 245–0066, Japan

    Toshihiko Ikeda

Authors
  1. Naoe Yamane
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  2. Zenzaburo Tozuka
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  3. Makiko Kusama
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  4. Kazuya Maeda
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  5. Toshihiko Ikeda
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  6. Yuichi Sugiyama
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Corresponding author

Correspondence to Yuichi Sugiyama.

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Yamane, N., Tozuka, Z., Kusama, M. et al. Clinical Relevance of Liquid Chromatography Tandem Mass Spectrometry as an Analytical Method in Microdose Clinical Studies. Pharm Res 28, 1963–1972 (2011). https://doi.org/10.1007/s11095-011-0423-8

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  • DOI: https://doi.org/10.1007/s11095-011-0423-8

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