Associations between plasma hydroxylated metabolite of itraconazole and serum creatinine in patients with a hematopoieti
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PHARMACOKINETICS AND DISPOSITION
Associations between plasma hydroxylated metabolite of itraconazole and serum creatinine in patients with a hematopoietic or immune-related disorder Yumi Imoto 1 & Takafumi Naito 1
&
Yukari Miyadera 1 & Takaaki Ono 2 & Junichi Kawakami 1
Received: 30 June 2020 / Accepted: 1 October 2020 # Springer-Verlag GmbH Germany, part of Springer Nature 2020
Abstract Purpose Serum markers of renal function have not been characterized in patients treated with itraconazole (ITZ). This study aimed to evaluate the associations between plasma ITZ and its hydroxylated metabolite (OH-ITZ) concentrations and serum markers of renal function in patients with hematopoietic or immune-related disorder. Methods This study enrolled 40 patients with hematopoietic or immune-related disorder who are receiving oral ITZ solution. Plasma concentrations of ITZ and OH-ITZ at 12 h after dosing were determined at steady state. Their relationships with serum levels of creatinine and cystatin C and their estimated glomerular filtration rate (eGFR) were evaluated. Results The free plasma concentration of ITZ had no correlation with serum creatinine and serum creatinine-based estimated glomerular filtration rate (eGFR-cre). The free plasma concentration of OH-ITZ was positively and negatively correlated with serum creatinine and eGFR-cre, respectively. The free plasma concentrations of ITZ and OH-ITZ had no association with serum cystatin C and serum cystatin C-based eGFR. Serum creatinine was higher by 16% after than before starting ITZ treatment, while eGFR-cre was lower by 9.3%. The serum creatinine ratio after/before ITZ treatment was positively correlated with the free plasma concentration of OH-ITZ. The patients co-treated with trimethoprim-sulfamethoxazole had higher serum creatinine. Concomitant glucocorticoid administration did not significantly alter serum cystatin C. Conclusions Patients with hematopoietic or immune-related disorder treated with oral ITZ had a higher level of serum creatinine. Although serum creatinine potentially increases in conjunction with the free plasma concentration of OH-ITZ, concomitant ITZ administration has a slight impact on the eGFR-cre level in clinical settings. Keywords Itraconazole . Metabolite . Pharmacokinetics . Creatinine . Renal function . Cystatin C
Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00228-020-03010-y) contains supplementary material, which is available to authorized users. * Takafumi Naito [email protected] 1
Department of Hospital Pharmacy, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu 431-3192, Japan
2
Division of Hematology, Internal Medicine 3, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu 431-3192, Japan
Abbreviations ITZ Itraconazole CYP Cytochrome P450 OH-ITZ Hydroxyitraconazole OATP Organic anion transporting polypeptide MATE Multidrug and toxic compound extrusion IC50 Half maximal inhibitory concentration OCT Organic cati
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