Vol.53 No.S-2 November 2005

A Clinical Trial of Voriconazole for Deep-seated Mycosis -An Uncontrolled Multicenter Study

Yoshihito Niki¹⁾, Minoru Yoshida²⁾, Kaoru Shimada³⁾, Shigeru Kohno⁴⁾, Tohru Masaoka⁵⁾, Hideyo Yamaguchi⁶⁾, Naoki Aikawa⁷⁾, Takeshi Mori⁸⁾, Masahiro Andoh⁹⁾, Koichiro Nakata¹⁰⁾, Koichiro Kudo¹¹⁾, Yukihiro Arai¹²⁾, Jin Takeuchi¹³⁾, Hideaki Mizoguchi¹⁴⁾, Kou Uchida¹⁵⁾, Hiroshige Mikamo¹⁶⁾, Katsunori Yanagihara⁴⁾, Yoshitsugu Miyazaki⁴⁾, Hideyuki Ikematsu¹⁷⁾, Rokuro Matsuoka¹⁸⁾, Koichiro Yoshida¹⁾, Akiyoshi Miwa¹⁹⁾, Shinichi Oka²⁰⁾, Masafumi Taniwaki²¹⁾, Masato Watanabe²²⁾, Shinji Motojima²³⁾, Mitsuru Konishi²⁴⁾, Shinichiro Okamoto²⁵⁾, Takahide Matsuda²⁶⁾, Takehisa Murakami²⁷⁾, Yutaka Nakashima²⁸⁾, Tomomitsu Hotta²⁹⁾, Yoshikazu Ito³⁰⁾, Nobuhiko Emi³¹⁾, Yoshitomo Mutoh³²⁾, Miki Nishimura³³⁾, Kazuhiro Kimura³⁴⁾, Tetsu Mizutani³⁵⁾, Kensuke Usuki³⁶⁾, Yasushi Takamatsu³⁷⁾, Junichi Kadota³⁸⁾, Osamu Miura³⁹⁾, Hisashi Sakamaki⁴⁰⁾, Masahiro Kami⁴¹⁾, Osamu Yamada⁴²⁾, Hideho Wada⁴³⁾, Noriko Usui⁴⁴⁾, Masami Nagai⁴⁵⁾, Yoshio Takesue⁴⁶⁾, Minoru Tanaka⁴⁷⁾, Fumihiko Kimura⁴⁸⁾, Atsuyuki Kurashima⁴⁹⁾, Masahiro Abe⁵⁰⁾, Hidetoshi Igari⁵¹⁾ and Takayuki Takahashi⁵²⁾

¹⁾Division of Respiratory Diseases, Department of Medicine, Kawasaki Medical School,
577 Matsushima, Kurashiki, Okayama, Japan
²⁾Forth Department of Internal Medicine, Teikyo University School of Medicine
³⁾Tokyo Senbai Hospital
⁴⁾Division of Molecular &； Microbiology, Department of Molecular Microbiology &； Immunology,
Nagasaki University Graduate School of Medicine
⁵⁾Osaka Medical Center for Cancer and Cardiovascular Diseases, Hospital
⁶⁾Teikyo University Institute of Medical Mycology
⁷⁾Department of Emergency and Critical Care Medicine, School of Medicine, Keio University
⁸⁾Division of Hematology, Department of Medicine, Juntendo University School of Medicine
⁹⁾Department of Internal Medicine, Tsuboi Hospital
¹⁰⁾Division of Respiratory Diseases, Toranomon Hospital
¹¹⁾Department of Chest Medicine, National Medical Center Hospital
¹²⁾Department of Hematology, Dokkyo University School of Medicine
¹³⁾First Department of Internal Medicine, Nihon University School of Medicine
¹⁴⁾The Department of Hematology, Tokyo Women's Medical University
¹⁵⁾Second Department of Internal Medicine, Toho University School of Medicine
¹⁶⁾Department of Obstetrics and Gynecology, Gifu University School of Medicine
¹⁷⁾Department of Internal Medicine, Haradoi Hospital
¹⁸⁾Department of Pulmonary Medicine, Showa General Hospital
¹⁹⁾Division of Hematology, International Medical Center of Japan
²⁰⁾The AIDS Clinical Center, Department of Clinical Research and Development,
International Medical Center of Japan
²¹⁾The Third Department of Internal Medicine, Kyoto Prefectural University of Medicine
²²⁾The Second Department of Internal Medicine, Mie University School of Medicine
²³⁾Department of General Internal Medicine, Kameda General Hospital
²⁴⁾The Second Department of Internal Medicine, Nara Medical School
²⁵⁾Division of Hematology, Keio University School of Medicine
²⁶⁾Department of Rheumatology and Allergy, St. Marianna University School of Medicine
²⁷⁾Forth Department of Internal Medicine, Teikyo University School of Medicine
²⁸⁾Forth Department of Internal Medicine, Teikyo University School of Medicine
²⁹⁾Division of Hematology and Rheumatology, The Department of Internal Medicine,
Tokai University School of Medicine
³⁰⁾The First Department of Internal Medicine, Tokyo Medical College
³¹⁾The First Department of Internal Medicine, Nagoya University School of Medicine
³²⁾The Department of Hematology, Toranomon Hospital
³³⁾The Second Department of Internal Medicine, Chiba University School of Medicine
³⁴⁾Department of Respiratory Medicine, Toho University School of Medicine
³⁵⁾Department of Infectious Diseases, Kitano Hospital, The Tazuke Kofukai Medical Research Institute
³⁶⁾Division of Hematology, NTT Kanto Medical Center
³⁷⁾The First Department of Internal Medicine, Fukuoka University School of Medicine
³⁸⁾The Second Department of Internal Medicine, Oita University School of Medicine
³⁹⁾Department of Hematology and Oncology, Graduate School of Medicine,
Tokyo Medical and Dental University
⁴⁰⁾Hematology Division, Tokyo Metropolitan Hospital
⁴¹⁾Hematopoietic Stem-Cell Transplantation unit, National Cancer Center Hospital
⁴²⁾Division of Hematology, Department of Internal Medicine, Kawasaki Medical School
⁴³⁾Division of Hematology, Department of Internal Medicine, Kawasaki Medical School
⁴⁴⁾Division of Hematology and Oncology, Department of Internal Medicine,
Jikei University School of Medicine
⁴⁵⁾First Department of Internal Medicine, Faculty of Medicine, Kagawa University
⁴⁶⁾The First Department of Surgery, Hiroshima University School of Medicine
⁴⁷⁾Department of Ophthalmology, Juntendo University Urayasu Hospital
⁴⁸⁾Third Department of Internal Medicine, National Defense Medical College
⁴⁹⁾The Department of Pulmonary Medicine, National Tokyo Hospital
⁵⁰⁾First Department of Internal Medicine, Tokushima University School of Medicine
⁵¹⁾Department of Chest Medicine, Institute of Pulmonary Cancer Research,
Chiba University School of Medicine
⁵²⁾Department of Hematology and Clinical Immunology, Kobe City General Hospital

Abstract

This was an uncontrolled multicenter study to assess the clinical usefulness (efficacy and safety) of voriconazole (VRCZ) for deep-seated mycosis.
Efficacy was assessed in 65 of 100 subjects given the study drug, while safety was assessed in 100 subjects.
For oral therapy, 300 mg of VRCZ was administered twice as the loading dose on Day 1, and patients then received 150-200 mg twice daily on subsequent treatment days. For intravenous therapy, 6 mg/kg of VRCZ was administered twice as the loading dose on Day 1, and the maintenance dose for subsequent treatment days was 3 mg/kg twice daily or in the case of severe mycosis, 4 mg/kg twice a day. When plasma VRCZ concentrations were equal to or greater than 2.5 μg/mL on Day 3 of oral and intravenous administration, dosages were decreased on Days 5-7. A switch from intravenous to oral formulation (switch therapy) was allowed after intravenous therapy had been given for at least 3 days. Treatment lasted 12 weeks. Global efficacy was 68.3% (28/41) for aspergillosis, 91.7% (11/12) for candidiasis, and 100% (8/8) for cryptococcosis.
Global efficacy for primary therapy was 91.2% (31/34) and that for salvage therapy 61.3% (19/31).
Eradication in the 65 cases evaluated for efficacy was 69.2% (9/13) for Aspergillus spp. and 91.7% (11/12) for Candida spp..
Treatment-related adverse events were reported in 78 of 100 cases. The most common adverse events were photophobia (25.0%), visual disturbance (24.0%), vomiting (8.0%), hepatic function abnormalities (8.0%), headache (8.0%), and increased γ-GTP (7.0%). Vision-related adverse events were transient and reversible in all cases. Most treatment-related adverse events were mild to moderate in severity.
No relationship was seen between plasma VRCZ concentrations and either the efficacy or safety of this drug.
These results indicate that VRCZ is useful for the treatment of severe or intractable deep-seated mycosis.

Key word

voriconazole, triazole antifungal agent, aspergillosis, candidiasis, cryptococcosis

Received

July 8, 2005

Accepted

September 28, 2005

Jpn. J. Chemother. 53 (S-2): 32-50, 2005