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Effect of aprepitant on the pharmacokinetics of the cyclin-dependent kinase inhibitor dinaciclib in patients with advanced malignancies

  • Clinical Trial Report
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Cancer Chemotherapy and Pharmacology Aims and scope Submit manuscript

Abstract

Purpose

Dinaciclib, a selective inhibitor of cyclin-dependent kinase (CDK) 1, CDK2, CDK5, and CDK9, is metabolized via CYP3A4. Aprepitant, a neurokinin-1 receptor antagonist for the prevention of chemotherapy-induced nausea and vomiting, is an inhibitor and inducer of CYP3A4. We conducted a randomized, crossover study to investigate the effects of single oral doses of aprepitant when coadministered with dinaciclib.

Methods

As part of a phase 1 dose-escalation trial, subjects with advanced malignancies were randomized into a 2-period, multi-cycle, crossover study to investigate the effect of single doses of oral aprepitant on the pharmacokinetics of 29.6 mg/m2 dinaciclib administered by 2-h intravenous infusion. During cycle 1 and cycle 2, subjects received dinaciclib with aprepitant in one cycle and dinaciclib without aprepitant in the other cycle; aprepitant was administered at a dose of 125 mg orally on day 1 and 80 mg orally on days 2 and 3, along with standard dosing regimens of ondansetron and dexamethasone.

Results

Twelve patients completed the study; T max occurred approximately 2 h after the initiation of the infusion. The percent geometric mean ratio (dinaciclib + aprepitant vs. dinaciclib alone) was 106 % (90 % confidence interval [CI] 89–126 %) and 111 % (90 % CI 93–132 %) for dinaciclib C max and AUC[I], respectively. The half-life and clearance of dinaciclib were similar, with or without aprepitant.

Conclusions

Coadministration of dinaciclib with aprepitant resulted in no clinically significant effect on the pharmacokinetics and did not alter the safety profile of dinaciclib in patients with advanced malignancies.

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Acknowledgments

The study was sponsored by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. (Whitehouse Station, NJ). Medical writing and editorial assistance were provided by Kakuri M. Omari, PhD, of Integrus Scientific, a division of Medicus International New York (New York, NY). This assistance was funded by Merck Sharp & Dohme Corp. The authors are fully responsible for all content and editorial decisions and received no financial support or other compensation related to the development of the manuscript.

Conflicts of interest

K. S. and P. S. own stock in Merck; R. B. was an employee of Merck and owned stock in Merck when the study was conducted; D. Z., M. M., G. S., J. P., A. T., B. K., and Y. Z. have no conflicts of interest to disclose.

Author information

Author notes

  1. Monica Mita

    Present address: Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA

  2. Jennifer Poon

    Present address: Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA

  3. Rajat Bannerji

    Present address: The Cancer Institute of New Jersey and Robert Wood Johnson Medical School, New Brunswick, NJ, USA

Authors and Affiliations

  1. Merck Sharp & Dohme Corp., Whitehouse Station, NJ, USA

    Da Zhang, Karen Small, Anjela Tzontcheva, Bhavna Kantesaria & Yali Zhu

  2. Early Drug Development Center, Dana-Farber Cancer Institute, Boston, MA, USA

    Geoffrey I. Shapiro

  3. Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, NJ, 07059, USA

    Paul Statkevich

Authors
  1. Da Zhang
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  2. Monica Mita
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  3. Geoffrey I. Shapiro
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  5. Karen Small
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  8. Yali Zhu
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Corresponding author

Correspondence to Paul Statkevich.

Additional information

Monica Mita and Geoffrey I. Shapiro contributed equally to this work.

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Zhang, D., Mita, M., Shapiro, G.I. et al. Effect of aprepitant on the pharmacokinetics of the cyclin-dependent kinase inhibitor dinaciclib in patients with advanced malignancies. Cancer Chemother Pharmacol 70, 891–898 (2012). https://doi.org/10.1007/s00280-012-1967-y

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  • DOI: https://doi.org/10.1007/s00280-012-1967-y

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