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Population Pharmacokinetic Analysis and Dosing Optimization of Prophylactic Fluconazole in Japanese Patients with Hematological Malignancy

We conducted population pharmacokinetic (PPK) analysis and Monte Carlo simulations to determine the appropriate prophylactic dose of fluconazole to prevent invasive candidiasis in patients with hematological malignancies. Patients receiving chemotherapy or hematopoietic stem cell transplantation at...

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Autores principales: Sakamoto, Yasutaka, Isono, Hikaru, Enoki, Yuki, Taguchi, Kazuaki, Miyazaki, Takuya, Kunimoto, Hiroyoshi, Koike, Hirofumi, Hagihara, Maki, Matsumoto, Kenji, Nakajima, Hideaki, Sahashi, Yukiko, Matsumoto, Kazuaki
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8618010/
https://www.ncbi.nlm.nih.gov/pubmed/34829262
http://dx.doi.org/10.3390/jof7110975
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author Sakamoto, Yasutaka
Isono, Hikaru
Enoki, Yuki
Taguchi, Kazuaki
Miyazaki, Takuya
Kunimoto, Hiroyoshi
Koike, Hirofumi
Hagihara, Maki
Matsumoto, Kenji
Nakajima, Hideaki
Sahashi, Yukiko
Matsumoto, Kazuaki
author_facet Sakamoto, Yasutaka
Isono, Hikaru
Enoki, Yuki
Taguchi, Kazuaki
Miyazaki, Takuya
Kunimoto, Hiroyoshi
Koike, Hirofumi
Hagihara, Maki
Matsumoto, Kenji
Nakajima, Hideaki
Sahashi, Yukiko
Matsumoto, Kazuaki
author_sort Sakamoto, Yasutaka
collection PubMed
description We conducted population pharmacokinetic (PPK) analysis and Monte Carlo simulations to determine the appropriate prophylactic dose of fluconazole to prevent invasive candidiasis in patients with hematological malignancies. Patients receiving chemotherapy or hematopoietic stem cell transplantation at Yokohama City University Hospital between November 2018 and March 2020 were included. Additionally, patients receiving oral fluconazole for prophylaxis were recruited. We set the free area under the curve/minimum inhibitory concentration (MIC) = 50 as the target and determined the largest MIC (breakpoint MIC) that could achieve more than 90% probability of target attainment. The blood fluconazole concentration of 54 patients (119 points) was used for PPK analysis. The optimal model was the one-compartment model with first-order administration and first-order elimination incorporating creatinine clearance (CLcr) as a covariate of clearance and body weight as a covariate of distribution volume. We conducted Monte Carlo simulation with fluconazole at 200 mg/day or 400 mg/day dosing schedules and patient body weight and CLcr ranging from 40 to 70 kg and 40–140 mL/min, respectively. The breakpoint MICs on the first dosing day and at steady state were 0.5–1.0 μg/mL and 1.0–2.0 μg/mL for 200 mg/day and 1.0–2.0 μg/mL and 2.0–4.0 μg/mL for 400 mg/day, respectively. The recommended dose was 400–700 mg/day for the loading dose and 200–400 mg/day for the maintenance dose. Our findings suggest that the optimal prophylactic dose of fluconazole in hematological malignancy patients depends on CLcr and body weight, and a sufficient loading and maintenance dose may be needed to completely prevent invasive candidiasis.
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spelling pubmed-86180102021-11-27 Population Pharmacokinetic Analysis and Dosing Optimization of Prophylactic Fluconazole in Japanese Patients with Hematological Malignancy Sakamoto, Yasutaka Isono, Hikaru Enoki, Yuki Taguchi, Kazuaki Miyazaki, Takuya Kunimoto, Hiroyoshi Koike, Hirofumi Hagihara, Maki Matsumoto, Kenji Nakajima, Hideaki Sahashi, Yukiko Matsumoto, Kazuaki J Fungi (Basel) Article We conducted population pharmacokinetic (PPK) analysis and Monte Carlo simulations to determine the appropriate prophylactic dose of fluconazole to prevent invasive candidiasis in patients with hematological malignancies. Patients receiving chemotherapy or hematopoietic stem cell transplantation at Yokohama City University Hospital between November 2018 and March 2020 were included. Additionally, patients receiving oral fluconazole for prophylaxis were recruited. We set the free area under the curve/minimum inhibitory concentration (MIC) = 50 as the target and determined the largest MIC (breakpoint MIC) that could achieve more than 90% probability of target attainment. The blood fluconazole concentration of 54 patients (119 points) was used for PPK analysis. The optimal model was the one-compartment model with first-order administration and first-order elimination incorporating creatinine clearance (CLcr) as a covariate of clearance and body weight as a covariate of distribution volume. We conducted Monte Carlo simulation with fluconazole at 200 mg/day or 400 mg/day dosing schedules and patient body weight and CLcr ranging from 40 to 70 kg and 40–140 mL/min, respectively. The breakpoint MICs on the first dosing day and at steady state were 0.5–1.0 μg/mL and 1.0–2.0 μg/mL for 200 mg/day and 1.0–2.0 μg/mL and 2.0–4.0 μg/mL for 400 mg/day, respectively. The recommended dose was 400–700 mg/day for the loading dose and 200–400 mg/day for the maintenance dose. Our findings suggest that the optimal prophylactic dose of fluconazole in hematological malignancy patients depends on CLcr and body weight, and a sufficient loading and maintenance dose may be needed to completely prevent invasive candidiasis. MDPI 2021-11-16 /pmc/articles/PMC8618010/ /pubmed/34829262 http://dx.doi.org/10.3390/jof7110975 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Sakamoto, Yasutaka
Isono, Hikaru
Enoki, Yuki
Taguchi, Kazuaki
Miyazaki, Takuya
Kunimoto, Hiroyoshi
Koike, Hirofumi
Hagihara, Maki
Matsumoto, Kenji
Nakajima, Hideaki
Sahashi, Yukiko
Matsumoto, Kazuaki
Population Pharmacokinetic Analysis and Dosing Optimization of Prophylactic Fluconazole in Japanese Patients with Hematological Malignancy
title Population Pharmacokinetic Analysis and Dosing Optimization of Prophylactic Fluconazole in Japanese Patients with Hematological Malignancy
title_full Population Pharmacokinetic Analysis and Dosing Optimization of Prophylactic Fluconazole in Japanese Patients with Hematological Malignancy
title_fullStr Population Pharmacokinetic Analysis and Dosing Optimization of Prophylactic Fluconazole in Japanese Patients with Hematological Malignancy
title_full_unstemmed Population Pharmacokinetic Analysis and Dosing Optimization of Prophylactic Fluconazole in Japanese Patients with Hematological Malignancy
title_short Population Pharmacokinetic Analysis and Dosing Optimization of Prophylactic Fluconazole in Japanese Patients with Hematological Malignancy
title_sort population pharmacokinetic analysis and dosing optimization of prophylactic fluconazole in japanese patients with hematological malignancy
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8618010/
https://www.ncbi.nlm.nih.gov/pubmed/34829262
http://dx.doi.org/10.3390/jof7110975
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