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Application of Modeling and Simulation to a Long-Term Clinical Trial: A Direct Comparison of Simulated Data and Data Actually Observed in Japanese Osteoporosis Patients Following 3-Year Ibandronate Treatment

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An Erratum to this article was published on 20 March 2015

Abstract

Ibandronate, a nitrogen-containing bisphosphonate, is a bone resorption inhibitor widely used to prevent and treat osteoporosis. To optimize the design for a long-term clinical study of ibandronate, modeling and simulation (M&S) was performed based on the result of population pharmacodynamic analysis using the data of a short-term clinical study. A population pharmacodynamic model was constructed by the urinary C-terminal telopeptide of type I collagen (uCTx) and the lumbar spine bone mineral density (BMD) data obtained in clinical studies, including a phase II study of Japanese osteoporosis patients treated with ibandronate for 6 months. Changes in BMD over a period of 3 years were simulated from the population pharmacodynamic parameters of the patients in this phase II study. The relationship between uCTx and BMD was well described by this modeling. The functions of disease progression and supplemental treatment were incorporated into the model to simulate a long-term clinical study with high accuracy. A long-term clinical study with a 3-year treatment was conducted after this M&S. The percentage change from baseline in observed BMD values were found to be similar to the prospectively simulated values. This study showed that M&S could be a useful and powerful tool for designing and conducting long-term clinical studies when carried out in the following sequence: (1) conduct a short-term clinical study; (2) perform M&S; and (3) conduct the long-term clinical study. Application of this procedure to various other treatment agents will establish the usefulness of M&S for long-term clinical studies and bring further efficiencies to drug development.

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Acknowledgments

The authors thank Dr. Ronald Gieschke and Dr. Bruno Reigner, F. Hoffmann-La Roche Ltd., for discussing the study results with them. The phase II study was sponsored by Chugai Pharmaceutical Co. Ltd, Japan. The phase II/III (MOVER) study was jointly funded by Chugai Pharmaceutical Co. Ltd. and Taisho Pharmaceutical Co. Ltd. Kiyohiko Nakai, Satofumi Iida, Masato Tobinai, Junko Hashimoto, and Takehiko Kawanishi have no conflicts of interest.

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Authors and Affiliations

  1. Clinical Research Planning Department, Chugai Pharmaceutical Co., Ltd, 2-1-1, Nihonbashi Muromachi, Chuo-ku, Tokyo, 103-8324, Japan

    Kiyohiko Nakai, Satofumi Iida, Masato Tobinai & Takehiko Kawanishi

  2. Primary Lifecycle Management Department, Chugai Pharmaceutical Co., Ltd, 2-1-1, Nihonbashi Muromachi, Chuo-ku, Tokyo, 103-8324, Japan

    Junko Hashimoto

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  1. Kiyohiko Nakai
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  2. Satofumi Iida
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  3. Masato Tobinai
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  5. Takehiko Kawanishi
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Correspondence to Kiyohiko Nakai.

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Nakai, K., Iida, S., Tobinai, M. et al. Application of Modeling and Simulation to a Long-Term Clinical Trial: A Direct Comparison of Simulated Data and Data Actually Observed in Japanese Osteoporosis Patients Following 3-Year Ibandronate Treatment. Clin Pharmacokinet 54, 295–304 (2015). https://doi.org/10.1007/s40262-014-0206-6

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  • DOI: https://doi.org/10.1007/s40262-014-0206-6

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