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Successful Empirical Antifungal Therapy of Intravenous Itraconazole with Pharmacokinetic Evidence in Pediatric Cancer Patients Undergoing Hematopoietic Stem Cell Transplantation

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Abstract

Background and Objectives

Empirical antifungal therapy prevents invasive fungal infections in patients with cancer. This study assessed the empirical efficacy of intravenous itraconazole in pediatric patients undergoing hematopoietic stem cell transplantation, and investigated the pharmacokinetics and clinical implications.

Methods

Oral itraconazole syrup was started (2.5 mg/kg twice daily) for prophylaxis, and patients with persistent neutropenic fever for more than 2 days were switched to intravenous itraconazole (5 mg/kg twice daily for 2 days for induction and 5 mg/kg daily for maintenance) as empirical treatment. Empirical antifungal efficacy was assessed retrospectively in 159 transplantations, and a full pharmacokinetic study was prospectively conducted in six of these patients. Successful antifungal efficacy was defined as the fulfillment of all components of a five-part composite end point.

Results

The overall empirical antifungal success rate fulfilling all criteria was 42.1 %. No death or drug-related serious adverse events occurred during the study. Mean trough plasma concentration of itraconazole after oral prophylaxis and intravenous induction were 577.2 and 1659.7 μg/L, respectively. Mean area under the concentration-time curve of itraconazole and its metabolite at steady state were 42,837 ± 24,746 μg·h/L and 63,094 ± 19,255 μg·h/L.

Conclusions

Intravenous itraconazole was effective and safe as an empirical antifungal agent in pediatric patients; this was due to the fast and satisfactory increase in drug concentration by switching from oral to intravenous therapy.

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Acknowledgments

This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MEST) (No. 2012R1A1A2008316). The authors thank Dr. Seo Hyun Yoon (Department of Clinical Pharmacology and Therapeutics, SNUH) and Ms. Ka-Heon Song (Clinical Research Institute, SNUH) for their assistance with drug concentration analysis.

Conflicts of interest

Hyery Kim, Donghoon Shin, Hyoung Jin Kang, Kyung-Sang Yu, Ji Won Lee, Sung Jin Kim, Min Sun Kim, Eun Sun Song, Mi Kyoung Jang, June Dong Park, In-Jin Jang, Kyung Duk Park, Hee Young Shin, and Hyo Seop Ahn have no potential conflicts of interest.

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    Authors and Affiliations

    1. Cancer Research Institute, Seoul National University College of Medicine, #28 Yongon-dong, Chongno-gu, Seoul, 110-744, Republic of Korea

      Hyery Kim, Hyoung Jin Kang, Ji Won Lee, Sung Jin Kim, Min Sun Kim, Eun Sun Song, Mi Kyoung Jang, Kyung Duk Park, Hee Young Shin & Hyo Seop Ahn

    2. Department of Pediatrics, Chung-Ang University College of Medicine, Seoul, Republic of Korea

      Hyery Kim

    3. Department of Pediatrics, Seoul National University College of Medicine, Seoul, Republic of Korea

      Hyoung Jin Kang, Ji Won Lee, Min Sun Kim, June Dong Park, Kyung Duk Park, Hee Young Shin & Hyo Seop Ahn

    4. Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine, #28 Yongon-dong, Chongno-gu, Seoul, 110-744, Republic of Korea

      Donghoon Shin, Kyung-Sang Yu & In-Jin Jang

    5. Cancer Center, Bundang Seoul National University Hospital, Seongnam, Republic of Korea

      Sung Jin Kim & Hyo Seop Ahn

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    Correspondence to Hyoung Jin Kang or Kyung-Sang Yu.

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    H. Kim and D. Shin contributed equally to this work. H. J. Kang and K.-S. Yu contributed equally to the supervision of this work and are the co-corresponding authors.

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    Kim, H., Shin, D., Kang, H.J. et al. Successful Empirical Antifungal Therapy of Intravenous Itraconazole with Pharmacokinetic Evidence in Pediatric Cancer Patients Undergoing Hematopoietic Stem Cell Transplantation. Clin Drug Investig 35, 437–446 (2015). https://doi.org/10.1007/s40261-015-0297-3

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