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Pharmacokinetics and Safety of Posaconazole Tablet Formulation in Chinese Participants at High Risk for Invasive Fungal Infection

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Abstract

Introduction

This study characterized the multidose pharmacokinetic (PK) characteristics of posaconazole tablets used as prophylactic antifungal therapy in Chinese patients with acute myelogenous leukemia (AML) at risk for invasive fungal infection (IFI).

Methods

Participants in this open-label, single-arm, phase 1b study received posaconazole 300 mg twice daily on day 1 and then once daily for up to 28 days. In the intensive PK sampling subgroup, posaconazole was administered under fasting conditions on days 1 and 8, and blood samples were regularly collected over 24 h. Trough PK sampling was conducted in all participants on days 1, 2, 3, 8, 14, 21, and 28 without regard for food intake. Population PK characteristics were predicted using PK modeling. Primary endpoints were steady-state average concentration (Cavg) and percentage of participants with steady-state Cavg (predicted and observed) > 500 ng/ml. Treatment safety and efficacy were secondary endpoints.

Results

Sixty-five adult Chinese participants were enrolled. On day 8, steady-state arithmetic mean Cavg was 1610 ng/ml (% coefficient of variation [%CV] 42.8%) in the intensive PK subgroup (n = 20). All participants achieved a steady-state Cavg > 500 ng/ml. Predicted Cavg (pCavg) was 1770 ng/ml (%CV 33.7%) in the total population (n = 64); 92.2% of participants had pCavg values ≥ 500 ng/ml (n = 59). The posaconazole tablet safety profile was consistent with that of the oral formulation, and the IFI rate was 3%.

Conclusion

In Chinese AML patients, the posaconazole 300-mg tablet provided PK data comparable with those of previous studies and was generally well tolerated and efficacious.

Clinical Trial Registration

ClinicalTrials.gov, NCT02387983.

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Acknowledgements

The authors thank the participants of the study.

Funding

The design, study conduct, and financial support for this research were provided by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. They have also funded the journals Rapid Service fee associated with manuscript publication.

Medical Writing and Editorial Assistance

Medical writing assistance, supported by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, was provided by Jennifer M. Kulak, PhD, of ApotheCom (Yardley, PA) in the preparation of this article.

Authorship

All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.

Authorship Contributions

KL, DW, JL, HC, TZ, HD, LC, and XMZ contributed to acquisition of the data and reviewing/revising the manuscript. HN contributed to acquisition of the data, interpretation of the results, and reviewing/revising the manuscript. EM contributed to analysis of the data and reviewing/revising the manuscript. GAW and HW contributed to study design, analysis of data, interpretation of results, and reviewing/revising the manuscript. JJ contributed to interpretation of results and reviewing/revising the manuscript. YQ contributed to analysis of the data. All authors reviewed the final version of the manuscript and agreed with its submission.

Disclosures

Kaiyan Liu, Depei Wu, Junmin Li, Hu Chen, Hongmei Ning, Ting Zhao, Haiping Dai, and Li Chen have no conflicts to disclose. Eric Mangin, Hetty Waskin, and Xu Min Zhao are employees of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA (MSD). Gregory A. Winchell is a subcontractor to Certara providing paid services to MSD. Jun Jiang and Yanping Qiu were employees of MSD at the time of the study. Hetty Waskin holds stock in Merck & Co., Inc., Kenilworth, NJ, USA, and is an author on a submitted patent application. Xumin Zhao has changed affiliation from Merck & Co., Inc., Kenilworth, NJ, USA, to Bayer Healthcare Company Limited.

Compliance with Ethics Guidelines

The study was conducted in accordance with the principles of Good Clinical Practice, and written informed consent was obtained from each participant. The protocol was reviewed and approved by independent ethics committees at all participating study centers (Peking University People’s Hospital, The First Affiliated Hospital of Soochow University, The 307th Hospital of Chinese People’s Liberation Army, and Shanghai Ruijin Hospital). This study was performed in accordance with the Helsinki Declaration of 1964 and its later amendments. Informed consent was obtained from all participants included in the study.

Data Availability

The data sets generated and/or analyzed during the current study are not publicly available but are available from http://engagezone.merck.com/ds_documentation.php. Requests for access to the clinical study data can be submitted through the EngageZone site or via email to dataaccess@merck.com.

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Authors and Affiliations

  1. Peking University People’s Hospital, Beijing, China

    Kaiyan Liu & Ting Zhao

  2. The First Affiliated Hospital of Soochow University, Suzhou, China

    Depei Wu & Haiping Dai

  3. Shanghai Ruijin Hospital, Beijing, China

    Junmin Li & Li Chen

  4. The 307th Hospital of Chinese People’s Liberation Army, Beijing, China

    Hu Chen & Hongmei Ning

  5. Merck & Co., Inc., Kenilworth, NJ, USA

    Eric Mangin, Hetty Waskin, Jun Jiang, Yanping Qiu & Xu Min Zhao

  6. Certara USA, Inc., Princeton, NJ, USA

    Gregory A. Winchell

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  1. Kaiyan Liu
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  2. Depei Wu
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  3. Junmin Li
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  8. Li Chen
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  12. Jun Jiang
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Correspondence to Kaiyan Liu.

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Liu, K., Wu, D., Li, J. et al. Pharmacokinetics and Safety of Posaconazole Tablet Formulation in Chinese Participants at High Risk for Invasive Fungal Infection. Adv Ther 37, 2493–2506 (2020). https://doi.org/10.1007/s12325-020-01341-x

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