Skip to main content
NCBI home page
Frontiers in Pharmacology logoLink to Frontiers in Pharmacology
. 2023 Feb 13;14:1126580. doi: 10.3389/fphar.2023.1126580

Factors influencing plasma concentration of voriconazole and voriconazole- N-oxide in younger adult and elderly patients

Lin Cheng 1,†, Zaiming Liang 1,†, Fang Liu 1, Ling Lin 1, Jiao Zhang 1, Linli Xie 1, Mingjie Yu 1,*, Fengjun Sun 1,*
PMCID: PMC9969092  PMID: 36860301

Abstract

Background: Voriconazole (VCZ) metabolism is influenced by many factors. Identifying independent influencing factors helps optimize VCZ dosing regimens and maintain its trough concentration (C0) in the therapeutic window.

Methods: We conducted a prospective study investigating independent factors influencing VCZ C0 and the VCZ C0 to VCZ N-oxide concentration ratio (C0/CN) in younger adults and elderly patients. A stepwise multivariate linear regression model, including the IL-6 inflammatory marker, was used. The receiver operating characteristic (ROC) curve analysis was used to evaluate the predictive effect of the indicator.

Results: A total of 463 VCZ C0 were analyzed from 304 patients. In younger adult patients, the independent factors that influenced VCZ C0 were the levels of total bile acid (TBA) and glutamic-pyruvic transaminase (ALT) and the use of proton-pump inhibitors. The independent factors influencing VCZ C0/CN were IL-6, age, direct bilirubin, and TBA. The TBA level was positively associated with VCZ C0 (ρ = 0.176, p = 0.019). VCZ C0 increased significantly when the TBA levels were higher than 10 μmol/L (p = 0.027). ROC curve analysis indicated that when the TBA level ≥4.05 μmol/L, the incidence of a VCZ C0 greater than 5 μg/ml (95% CI = 0.54–0.74) (p = 0.007) increased. In elderly patients, the influencing factors of VCZ C0 were DBIL, albumin, and estimated glomerular filtration rate (eGFR). The independent factors that affected VCZ C0/CN were eGFR, ALT, γ-glutamyl transferase, TBA, and platelet count. TBA levels showed a positive association with VCZ C0 (ρ = 0.204, p = 0.006) and C0/CN (ρ = 0.342, p < 0.001). VCZ C0/CN increased significantly when TBA levels were greater than 10 μmol/L (p = 0.025). ROC curve analysis indicated that when the TBA level ≥14.55 μmol/L, the incidence of a VCZ C0 greater than 5 μg/ml (95% CI = 0.52–0.71) (p = 0.048) increased.

Conclusion: TBA level may serve as a novel marker for VCZ metabolism. eGFR and platelet count should also be considered when using VCZ, especially in elderly patients.

Keywords: voriconazole, voriconazole-N-oxide, total bile acid, platelet count, estimated glomerular filtration rate, IL-6

Introduction

Invasive fungal infections (IFIs) remain a clinical problem with high morbidity and mortality despite recent advances in diagnosis and treatment (Jenks et al., 2020). Common pathogens of IFIs are Candida, Cryptococcus, Aspergillus, and Mucormycetes. Except for patients with underlying hematologic malignancies, solid organ transplant recipients, and critically ill patients, high rates of IFIs and mortality are also observed among patients 65 years or older (Vallabhaneni et al., 2017; Matthaiou et al., 2018; Hesstvedt et al., 2019; Tsay et al., 2020). Voriconazole (VCZ) is an essential drug for treating IFIs, especially those caused by Aspergillus and Candida. It is a first-line therapy for patients with invasive Aspergillosis (Ullmann et al., 2018). However, VCZ has a narrow therapeutic range. A trough level of 1–5.5 mg/L is recommended for most European patients on VCZ prophylaxis or treatment (Ullmann et al., 2018), while a range of 0.5–5 mg/L is considered adequate for Chinese patients (Chen et al., 2018). Maintaining VCZ trough concentration (C0) in the therapeutic range is crucial in enhancing its treatment effect.

VCZ exhibits non-linear pharmacokinetics with large interindividual and intraindividual variabilities (Purkins et al., 2002; Theuretzbacher et al., 2006). Many factors influence VCZ C0, such as age, sex, VCZ dose and administration route, albumin, total bilirubin (TBIL), glutamic-pyruvic transaminase (ALT), glutamic-oxalacetic transaminase (AST), γ-glutamyl transferase (γ-GT), CYP2C19 gene polymorphisms, and inflammatory state. (Vanstraelen et al., 2014; Niioka et al., 2017; Veringa et al., 2017). However, the specificity of each index has certain limitations. Both clinical symptoms and test results must be considered to diagnose and treat infectious diseases. VCZ dosing regimens also require modification according to patients’ conditions.

Our previous study found that VCZ C0 in elderly patients was significantly higher than in younger adult patients. The proportion of patients with C0 greater than 5 mg/L was higher in older adults (Cheng et al., 2020). VCZ C0 in elderly patients was not significantly affected by CYP2C19 polymorphisms (Shang et al., 2020). Inflammation could affect liver function, C0, and the concentration ratio of VCZ C0 to VCZ N-oxide (C0/CN) in younger and older patients (Liang et al., 2022). Therefore, disease state and patient status could confer significant dynamic markers that contribute to the fluctuation of VCZ concentrations (Chantharit et al., 2020).

According to the US Food and Drug Administration Adverse Event Reporting System (2004–2021 data), the VCZ-induced liver injury ratio is 32.45% (Zhou et al., 2022). Intrinsic and idiosyncratic drug-induced hepatotoxicity causes alterations in bile acid homeostasis (Mosedale and Watkins, 2017). Thus, the total bile acid (TBA) level can influence VCZ metabolism. Platelets are key effector cells for inflammatory responses and have particular advantages (Jenne et al., 2013). Platelet count was one of the determinants of VCZ C0 in kidney transplant recipients (Zhao Y. C. et al., 2021). VCZ clearance was also significantly associated with platelet count in patients with liver dysfunction (Tang et al., 2019; Tang et al., 2021). The worsening of renal function was significantly associated with a cumulative dose of intravenous VCZ (≥400 mg/kg) (Yasu et al., 2018). Elderly patients often have impaired liver function, renal function, and chronic inflammation induced by chronic disease conditions. Therefore, we hypothesized that platelet count and renal function might affect VCZ metabolism in elderly patients.

This study aimed to identify the factors affecting VCZ C0 and C0/CN in younger adults and elderly patients using the stepwise multivariate linear regression model. In addition to the influencing factors reported in the literature, the TBA, IL-6, platelet count, hemoglobin, and renal function indexes were also included in the study.

Materials and methods

Patients and study design

A single-center prospective study was conducted from January 2018 to June 2022. The study analyzed patients who received both VCZ prophylaxis and treatment. The inclusion criteria were patients who: (a) received VCZ therapeutic drug monitoring (TDM); (b) aged ≥18 years; (c) with steady-state VCZ C0 ≥ 0.4 μg/ml; (d) with available IL-6 concentration data measured on the same day of VCZ C0 measurement (IL-6 level was routinely detected in our hospital); (e) with available routine blood, liver function, and renal function results measured on the same day of VCZ C0 measurement; and (f) agreed to the use of their blood samples for VCZ CN determination and signed informed consent forms.

This study was approved by the Ethics Committee of the First Affiliated Hospital of the Army Medical University. Patients were divided into two cohorts according to age: the elderly cohort (≥60 years) and the younger adult cohort (<60 years).

Data collection

The following data were collected from the medical chart: (a) demographic and clinical characteristics, including age, sex, weight, underlying diseases, fungal infection, VCZ dose and administration route, and combined use of proton-pump inhibitors (PPIs); (b) inflammation marker IL-6 levels; (c) routine blood examination indices, including hemoglobin levels and platelet count; (d) liver function indices, including alkaline phosphatase (ALP), ALT, AST, γ-GT, TBA, albumin, TBIL, direct bilirubin (DBIL), and indirect bilirubin (IBIL) levels; and (e) renal function indices, including urea nitrogen, creatinine levels, and estimated glomerular filtration rate (eGFR). VCZ dosing was adjusted according to the TDM result at the VCZ C0 measurement.

VCZ C0 and VCZ CN determination

VCZ C0 was measured routinely in the clinic. The steady state of VCZ C0 was defined as the concentration obtained after 3 days of intravenous VCZ therapy (a loading dose of 6 mg/kg) or oral VCZ therapy (a loading dose of 400 mg) or the concentration obtained after 5 days of VCZ therapy without a loading dose. VCZ N-oxide is the primary metabolite in plasma, accounting for 72% of circulating VCZ metabolites (Geist et al., 2013). The plasma VCZ C0/CN ratio may provide information about VCZ clearance. Therefore, the VCZ CN was detected. VCZ CN was measured together with VCZ C0 using liquid chromatography-tandem mass spectrometry (LC-MS/MS) as previously described (Shang et al., 2020). The limit of detection (LOD) of VCZ and VCZ N-oxide was 8 ng/ml and 10 ng/ml, respectively. The lower limit of quantification (LLOQ) of VCZ and VCZ N-oxide were both 400 ng/ml.

Statistical analysis

IBM SPSS 19.0 (IBM Corp., Armonk, NY, USA) was used to perform the analysis. Categorical data were compared with the chi-square test. Data that do not conform to a normal distribution are represented by the median and interquartile range (IQR). Data from the two cohorts were compared using independent sample t-tests and Mann-Whitney U tests. A stepwise multivariate linear regression model was used to identify the factors influencing the VCZ C0 and C0/CN ratios.

A total of 20 factors were used in the analysis, including sex, age, route of administration of VCZ, VCZ dose, combined use of PPIs, platelet count, and levels of hemoglobin, ALP, ALT, AST, γ-GT, TBA, albumin, TBIL, DBIL, IBIL, urea nitrogen, creatinine, eGFR, and IL-6. Additionally, the Spearman correlation test was performed to assess the association of the TBA level with VCZ C0 and VCZ C0/CN. The receiver operating characteristic (ROC) curve analysis was used to evaluate the predictive effect of indicators. Covariates with a p-value < 0.1 in the univariate analysis were entered into the multivariate analysis. A p-value < 0.05 was considered statistically significant.

Results

Younger adult patients

A total of 161 younger adult patients were included, with 229 VCZ C0 and 102 VCZ C0/CN. The primary baseline diseases were pneumonia, kidney disease, and leukemia. Almost a third of the patients had negative fungus detection results. Most patients received VCZ intravenously, with a dose of 3.6 ± 0.9 mg/kg, twice daily. Almost half of the patients received PPIs when taking VCZ (Table 1). The percentages of ALP, ALT, AST, TBA, albumin, TBIL, and DBIL within the normal range were 58.3%, 53.4%, 50.0%, 75.7%, 69.3%, 71.9%, and 61.6%, respectively (Table 2).

TABLE 1.

Demographic and clinical chacteristics of patients in the two cohorts.

Variable Younger adult cohort (n = 161) Elderly cohort (n = 143) p-value
Sex — — 0.001
Male (n [%]) 96 (59.6) 110 (76.9) —
Female (n [%]) 65 (40.4) 33 (23.1) —
Age (y) 43 ± 12 72 ± 8 <0.001
Underlying diseases — — —
Leukemia (no. [%]) 44 (27.3) 9 (6.3) —
Hypertension (no. [%]) 40 (24.8) 59 (41.3) —
Diabetes mellitus (no. [%]) 23 (14.3) 44 (30.8) —
Coronary heart disease (no. [%]) 2 (1.2) 18 (12.6) —
Kidney disease (no. [%]) 69 (42.9) 53 (37.1) —
Pneumonia (no. [%]) 97 (60.2) 113 (79.0) —
Fungus category —
Aspergillus (no. [%]) 29 (18.0) 36 (25.2) —
Saccharomycetes (no. [%]) 14 (8.7) 21 (14.7) —
Monilia (no. [%]) 26 (16.1) 33 (23.1) —
Unidentified fungi (no. [%]) 30 (18.6) 27 (18.9) —
Others (no. [%]) 5 (3.1) 1 (0.7) —
Negative (no. [%]) 58 (36.0) 34 (23.8) —
Route of administration — — 0.115
Intravenous (n [%]) 130 (80.7) 125 (87.4) —
Oral (n [%]) 31 (19.3) 18 (12.6) —
VCZ dose (mg/kg/dose) 3.6 ± 0.9 3.4 ± 0.9 0.023
Use of PPI 84 (52.2) 80 (55.9) 0.510
Open in a new tab

A patient may have several underlying diseases or fungus categories. Abbreviations: PPI, proton-pump inhibitor.

TABLE 2.

Laboratory data of patients in the two cohorts.

Variable Younger adult cohort (n = 229) Elderly cohort (n = 234) p-value
Voriconazole C0 (0.5–5.0 μg/ml) 3.00 (1.60, 4.81) 3.64 (2.12, 5.50) 0.027
Voriconazole C0/CN 1.33 (0.67, 3.11) 1.85 (0.85, 3.23) 0.307
IL-6 (0–7 ng/L) 23.9 (6.1, 75.0) 39.9 (15.9, 106.8) 0.001
Platelet count (125–350 ×109/L) 113 (39, 211) 169 (96, 255) <0.001
Hemoglobin (115–150 g/L) 87.6 ± 19.3 93.8 ± 19.0 0.001
Liver function
 ALP (38–126 U/L) 100.0 (73.5, 147.9) 114.7 (80.0, 159.0) 0.170
 ALT (13–69 U/L) 22.0 (10.4, 46.0) 22.0 (12.0, 37.9) 0.542
 AST (15–46 U/L) 30.9 (18.3, 57.0) 36.8 (24.1, 54.1) 0.068
 γ-GT (12–58 U/L) 69.4 (35.0, 151.2) 86.5 (43.8, 169.6) 0.082
 TBA (0–10 μmol/L) 4.4 (2.2, 9.8) 5.6 (3.0, 12.0) 0.015
 Albumin (30–50 g/L) 33.0 ± 5.6 33.1 ± 5.1 0.870
 TBIL (3–22 μmol/L) 13.0 (8.9, 23.8) 14.1 (9.8, 22.7) 0.333
 DBIL (0–6 μmol/L) 3.8 (1.7, 8.7) 4.6 (2.5, 10.2) 0.069
 IBIL (3–16 μmol/L) 8.7 (5.9, 14.0) 9.1 (6.8, 12.9) 0.436
Renal Function
 Urea nitrogen (1.7–8.3 mmol/L) 9.2 (6.0, 14.1) 12.6 (5.5, 20.0) 0.032
 Creatinine (59–104 μmol/L) 81.2 (52.2, 151.5) 75.2 (53.8, 126.0) 0.555
 eGFR (80–120 ml/min) 91.7 (41.0, 119.7) 83.9 (46.1, 109.4) 0.445
Open in a new tab

Data that do not conform to a normal distribution are represented by the median (interquartile range). Abbreviations: C0, trough concentrations of voriconazole; CN, trough concentrations of voriconazole-N-oxide; IL-6, interleukin-6; ALP, alkaline phosphatase; ALT, glutamic-pyruvic transaminase; AST, glutamic-oxalacetic transaminase; γ-GT, γ-glutamyl transferase; TBA, total bile acid; TBIL, total bilirubin; DBIL, direct bilirubin; IBIL, indirect bilirubin; eGFR, estimated glomerular filtration rate.

The independent influencing factors of VCZ C0 were levels of TBA and ALT and the use of PPIs. The independent influencing factors of VCZ C0/CN were IL-6, age, DBIL, and TBA levels (Table 3). TBA values showed a positive association with VCZ C0 (ρ = 0.176, p = 0.019) but not with VCZ C0/CN (ρ = 0.114, p = 0.305) (Figure 1). As shown in Figure 2, VCZ C0 increased significantly when TBA levels were higher than 10 μmol/L (p = 0.027). The analysis of the ROC curve indicated that TBA levels of ≥4.05 μmol/L, as well as the platelet count less than 31, increased the incidence of VCZ C0 greater than 5 μg/ml (95% CI = 0.54–0.74) (p = 0.007) (Figure 3). The ROC curve was not used for C0/CN due to the lack of a clinically significant threshold.

TABLE 3.

Influencing factor of VCZ C0 and C0/CN in younger adult patients.

VCZ C0 VCZ C0/CN
Factor OR (95% CI) Standardized coefficients p-Value Factor OR (95% CI) Standardized coefficients p-Value
Constant 5.074 (3.582, 6.565) — <0.001 Constant −2.030 (−4.059, 0) — 0.050
TBA 0.049 (0.029, 0.068) 0.428 <0.001 IL-6 0.002 (0.001, 0.002) 0.304 0.004
ALT −0.016 (−0.029, −0.004) −0.216 0.012 Age 0.089 (0.046, 0.132) 0.445 <0.001
PPI −0.968 (−1.844, −0.092) −0.180 0.031 DBIL 0.132 (0.067, 0.197) 0.684 <0.001
— — — — TBA −0.057 (−0.108, −0.006) −0.361 0.030
Open in a new tab

Abbreviations: TBA, total bile acid; ALT, glutamic-pyruvic transaminase; PPI, proton-pump inhibitor; DBIL, direct bilirubin.

FIGURE 1.

FIGURE 1

Open in a new tab

Association of total bile acid (TBA) level with voriconazole (VCZ) trough concentration (C0) and VCZ-to-VCZ N-oxide concentration ratio (C0/CN). (A). The TBA level was positively associated with VCZ C0 in younger adult patients; (B). There was no association between TBA level and VCZ C0/CN in younger adult patients; (C). There was a positive association between TBA level and VCZ C0 in elderly patients; (D). The TBA level was positively associated with VCZ C0/CN in elderly patients.

FIGURE 2.

FIGURE 2

Open in a new tab

Distribution of voriconazole (VCZ) trough concentration (C0) and the VCZ-to-VCZ N-oxide concentration ratio (C0/CN) according to total bile acid (TBA) level. (A). VCZ C0 in younger adult patients was significantly increased when TBA levels were higher than 10 μmol/L; (B). VCZ C0/CN in younger adult patients was similar when TBA levels were between 0 and 10 μmol/L and higher than 10 μmol/L; (C). VCZ C0 in elderly patients was similar when TBA levels were between 0 and 10 μmol/L and greater than 10 μmol/L; (D). VCZ C0/CN in elderly patients increased significantly when TBA levels were higher than 10 μmol/L. # p < 0.05.

FIGURE 3.

FIGURE 3

Open in a new tab

Receiver operating characteristic (ROC) curve to predict voriconazole trough concentrations greater than 5 μg/ml according to the total bile acid level (A), platelet count (B), and estimated glomerular filtration rate (C) in younger adult patients.

Elderly patients

A total of 143 elderly patients were included, with 234 VCZ C0 and 131 VCZ C0/CN. The primary baseline diseases were pneumonia, hypertension, and kidney disease. Thirty-four patients (23.8%) had negative fungi detection results. The proportion of men in the elderly cohort was higher than that in the younger adult cohort (p = 0.001). The route of VCZ administration in patients in the two cohorts was similar (p > 0.05). In contrast, the dose of VCZ in the elderly cohort was significantly lower than that in the younger adult cohort (p < 0.001) (Table 1).

VCZ C0 in the elderly cohort was significantly higher than that in the younger adult cohort (p < 0.05), while the VCZ C0/CN ratio in the two cohorts was similar (p > 0.05). The percentages of ALP, ALT, AST, TBA, albumin, TBIL, and DBIL within the normal range were 57.9%, 67.5%, 58.4%, 67.8%, 73.4%, 71.6%, and 59.5%, respectively. The levels of IL-6, platelet count, hemoglobin, TBA, and urea nitrogen in the elderly cohort were significantly higher than those of the younger adult cohort (p < 0.05) (Table 2).

The independent influencing factors of VCZ C0 were the levels of DBIL, albumin, and eGFR. The independent influencing factors of VCZ C0/CN were eGFR, ALT, γ-GT, TBA, and platelet count (Table 4). The TBA level showed a positive association with VCZ C0 (ρ = 0.204, p = 0.006) and C0/CN (ρ = 0.342, p < 0.001), respectively (Figure 1). VCZ C0/CN significantly increased when TBA levels were higher than 10 μmol/L (p = 0.025) (Figure 2). ROC curve analysis indicated that when the TBA level ≥14.55 μmol/L, the incidence of a VCZ C0 greater than 5 μg/ml (95% CI = 0.52–0.71) (p = 0.048) increased (Figure 4).

TABLE 4.

Influencing factor of VCZ C0 and C0/CN in elderly patients.

VCZ C0 VCZ C0/CN
Factor OR (95% CI) Standardized coefficients p-Value Factor OR (95% CI) Standardized coefficients p-Value
Constant 10.112 (5.497, 14.726) — <0.001 Constant 3.736 (2.789, 4.683) — <0.001
DBIL 0.071 (0.027, 0.115) 0.307 0.002 eGFR −0.014 (−0.022, −0.007) −0.382 <0.001
Albumin −0.160 (−0.288, −0.031) −0.233 0.016 ALT 0.044 (0.026, 0.061) 0.462 <0.001
eGFR −0.018 (−0.032, −0.003) −0.235 0.016 γ-GT −0.006 (−0.008, −0.003) −0.398 <0.001
— — — — TBA 0.022 (0.004, 0.041) 0.230 0.019
— — — — Platelet count −0.003 (−0.006, 0) −0.224 0.026
Open in a new tab

Abbreviations: DBIL, direct bilirubin; eGFR, estimated glomerular filtration rate; ALT, glutamic-pyruvic transaminase; γ-GT, γ-glutamyl transferase; TBA, total bile acid.

FIGURE 4.

FIGURE 4

Open in a new tab

Receiver operating characteristic (ROC) curve to predict voriconazole trough concentrations greater than 5 μg/ml according to the total bile acid level (A), platelet count (B), and estimated glomerular filtration rate (C) in elderly patients.

Discussion

VCZ-induced adverse reactions are generally considered the main reason for drug discontinuation and treatment failure associated with C0 (Jin et al., 2016; Hamada et al., 2020). Our previous study also showed a considerable number of VCZ C0 greater than 5 μg/ml, with a ratio of 23.4% in the younger adult cohort and 31.3% in the elderly cohort (Cheng et al., 2020). Therefore, it is crucial to investigate factors affecting VCZ metabolism. A significant correlation was found between VCZ C0 and age (Allegra et al., 2020; Bolcato et al., 2021). Niioka et al. found that older Japanese patients had higher VCZ C0/CN ratios (Niioka et al., 2017). Age was also a predictor of VCZ trough levels >5 μg/ml (Chen et al., 2022). Therefore, we investigated the factors affecting VCZ C0 and C0/CN in younger and elderly patients.

Our previous study found that IL-6 levels were associated with the VCZ C0/CN ratio in both younger and elderly patients (r = 0.355, p = 0.003; r = 0.386, p = 0.001). Therefore, this study included IL-6 as an inflammatory marker. IL-6 can directly target liver cells and down-regulate CYP2C19 and CYP3A4 gene expression during inflammation (Li et al., 2014; Klein et al., 2015), affecting VCZ metabolism. Our results showed that IL-6 level was an independent influencing factor of VCZ C0/CN in younger adults, which further confirmed the results of our previous study (Cheng et al., 2020; Liang et al., 2022).

Data on the effect of TBA on VCZ metabolism are limited. In the current study, TBA level was the independent influencing factor of VCZ C0 and C0/CN in younger adult patients and the independent influencing factor of C0/CN in older patients. TBA can effectively reflect the liver cell injury and the secretion and synthesis function of liver cells. TBA levels rise before the increase of bilirubin, which may partially explain our findings. Furthermore, the ROC curve identified the good predictive effects of TBA for VCZ C0 greater than 5 μg/ml. Our results indicate that TBA could be a good predictor of VCZ C0 in younger adult patients.

Platelets emerge as key players in inflammation and are key elements in the early phases of the inflammatory response (Nicolai and Massberg, 2020; Portier and Campbell, 2021). Accumulating evidence demonstrates that platelets contribute to the initiation and propagation of both local and systemic inflammatory processes (Manne et al., 2017). Since platelet count is routinely measured at our hospital, it was chosen as a key element in the inflammatory response. C-reactive protein (CRP) is an inflammatory marker commonly investigated in association with VCZ C0 and VCZ C0/CN in IFI patients (Dote et al., 2016; Encalada Ventura et al., 2016; Veringa et al., 2017; Vreugdenhil et al., 2018). We did not include CRP in this study due to the limited CRP data in the elderly. We also omitted procalcitonin because its association with VCZ C0/CN was insignificant in our previous study (Liang et al., 2022). Our results showed that platelet count was an independent influencing factor of VCZ C0/CN in elderly individuals. Therefore, platelet count could be considered in patients on VCZ therapies.

Liver function is generally considered to influence VCZ metabolism. VCZ is bound to albumin. Decreased albumin levels increase the unbound fraction of VCZ (Vanstraelen et al., 2014). Serum albumin and γ-GT levels were significantly correlated with the VCZ clearance rate (Chantharit et al., 2020). This study found that albumin level was an independent influencing factor of VCZ C0, and the γ-GT level was an independent influencing factor of VCZ C0/CN in elderly patients. Plasma TBIL concentration significantly influenced VCZ protein-protein binding (Vanstraelen et al., 2014). The TBIL level was associated with VCZ clearance in IFI patients with liver dysfunction (Tang et al., 2021). TBIL level was also considered an independent factor influencing VCZ C0 (Cheng et al., 2020; Zeng et al., 2020; Zhao Y. et al., 2021). However, our results showed that levels of DBIL but not TBIL influenced VCZ C0 and C0/CN. The liver is rich in a smooth endoplasmic reticulum (ER) equipped with enzymes that metabolize several drugs, including VCZ. DBIL is bioconverted to IBIL in the ER. DBIL levels may reflect the state of the ER and then exhibit an association with the metabolism of VCZ.

We found that eGFR was an independent influencing factor of VCZ C0 and VCZ C0/CN in elderly individuals. Our results showed that the eGFR in the elderly cohort was lower than that in the younger adult cohort, indicating an impaired renal function in the elderly cohort. Although VCZ dose adjustment is not recommended for patients with renal impairment, we should still pay attention to its use in the elderly based on our results. Furthermore, the degree of inflammation in the elderly cohort was more severe than in the younger adult cohort, with impaired liver and kidney function. Therefore, the use of VCZ in elderly patients should be monitored.

CYP2C19, CYP3A4, and CYP2C9 enzymes metabolize PPIs. The combined use of PPIs with VCZ can affect VCZ concentration (Yan et al., 2018). PPIs also significantly affected VCZ C0 in younger adult patients in our study.

This study has several limitations. First, we did not include samples with VCZ C0 lower than 0.4 mg/L because the LLOQ of VCZ and VCZ N-oxide were both 400 ng/ml. Second, although the polymorphisms of CYP2C19*2 and *3 are critical for examining the pharmacokinetics of VCZ (Moriyama et al., 2017), the CYP2C19 genotypes were not assessed since testing is not routinely performed. Finally, this study had a relatively small sample size. A large multicenter, prospective study is needed to confirm our results.

In conclusion, we report for the first time that TBA, eGFR, and platelet count were associated with VCZ C0 and C0/CN. Furthermore, the TBA level had a good predictive effect on VCZ C0 in younger adult patients and may serve as a novel marker of VCZ metabolism. eGFR and platelet count should also be considered when using VCZ, especially in elderly patients.

Funding Statement

This study was supported by the Medical Research Project of Science and Health of Chongqing (2021MSXM218).

Data availability statement

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

Ethics statement

The studies involving human participants were reviewed and approved by Ethics Committee of the First Affiliated Hospital of Army Medical University. The patients/participants provided their written informed consent to participate in this study.

Author contributions

LC and FS designed the study, performed the data analysis, and drafted the manuscript. ZL searched the data and performed the data analysis. MY performed the detection. FL, LL, JZ, and LX searched the data. All authors approved the final version of the manuscript.

Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Publisher’s note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

References

  1. Allegra S., De Francia S., De Nicolo A., Cusato J., Avataneo V., Manca A., et al. (2020). Effect of gender and age on voriconazole trough concentrations in Italian adult patients. Eur. J. Drug Metab. Pharmacokinet. 45 (3), 405–412. 10.1007/s13318-019-00603-6 [DOI] [PubMed] [Google Scholar]
  2. Bolcato L., Khouri C., Veringa A., Alffenaar J. W. C., Yamada T., Naito T., et al. (2021). Combined impact of inflammation and pharmacogenomic variants on voriconazole trough concentrations: A meta-analysis of individual data. J. Clin. Med. 10 (10), 2089. 10.3390/jcm10102089 [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Chantharit P., Tantasawat M., Kasai H., Tanigawara Y. (2020). Population pharmacokinetics of voriconazole in patients with invasive aspergillosis: Serum albumin level as a novel marker for clearance and dosage optimization. Ther. Drug Monit. 42 (6), 872–879. 10.1097/FTD.0000000000000799 [DOI] [PubMed] [Google Scholar]
  4. Chen C., Xu T., Zhou K., Zhu S. (2022). Factors affecting voriconazole concentration to dose ratio changes according to route of administration. Eur. J. Hosp. Pharm. ejhpharm-2021-003173. 10.1136/ejhpharm-2021-003173 [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Chen K., Zhang X., Ke X., Du G., Yang K., Zhai S. (2018). Individualized medication of voriconazole: A practice guideline of the division of therapeutic drug monitoring, Chinese pharmacological society. Ther. Drug Monit. 40 (6), 663–674. 10.1097/FTD.0000000000000561 [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Cheng L., Xiang R., Liu F., Li Y., Chen H., Yao P., et al. (2020). Therapeutic drug monitoring and safety of voriconazole in elderly patients. Int. Immunopharmacol. 78, 106078. 10.1016/j.intimp.2019.106078 [DOI] [PubMed] [Google Scholar]
  7. Dote S., Sawai M., Nozaki A., Naruhashi K., Kobayashi Y., Nakanishi H. (2016). A retrospective analysis of patient-specific factors on voriconazole clearance. J. Pharm. Health Care Sci. 2, 10. 10.1186/s40780-016-0044-9 [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Encalada Ventura M. A., van Wanrooy M. J., Span L. F., Rodgers M. G., van den Heuvel E. R., Uges D. R., et al. (2016). Longitudinal analysis of the effect of inflammation on voriconazole trough concentrations. Antimicrob. Agents Chemother. 60 (5), 2727–2731. 10.1128/AAC.02830-15 [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Geist M. J., Egerer G., Burhenne J., Riedel K. D., Weiss J., Mikus G. (2013). Steady-state pharmacokinetics and metabolism of voriconazole in patients. J. Antimicrob. Chemother. 68 (11), 2592–2599. 10.1093/jac/dkt229 [DOI] [PubMed] [Google Scholar]
  10. Hamada Y., Ueda T., Miyazaki Y., Nakajima K., Fukunaga K., Miyazaki T., et al. (2020). Effects of antifungal stewardship using therapeutic drug monitoring in voriconazole therapy on the prevention and control of hepatotoxicity and visual symptoms: A multicentre study conducted in Japan. Mycoses 63 (8), 779–786. 10.1111/myc.13129 [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Hesstvedt L., Gaustad P., Muller F., Torp Andersen C., Brunborg C., Mylvaganam H., et al. (2019). The impact of age on risk assessment, therapeutic practice and outcome in candidemia. Infect. Dis. (Lond) 51 (6), 425–434. 10.1080/23744235.2019.1595709 [DOI] [PubMed] [Google Scholar]
  12. Jenks J. D., Cornely O. A., Chen S. C., Thompson G. R., 3rd, Hoenigl M. (2020). Breakthrough invasive fungal infections: Who is at risk? Mycoses 63 (10), 1021–1032. 10.1111/myc.13148 [DOI] [PubMed] [Google Scholar]
  13. Jenne C. N., Urrutia R., Kubes P. (2013). Platelets: Bridging hemostasis, inflammation, and immunity. Int. J. Lab. Hematol. 35 (3), 254–261. 10.1111/ijlh.12084 [DOI] [PubMed] [Google Scholar]
  14. Jin H., Wang T., Falcione B. A., Olsen K. M., Chen K., Tang H., et al. (2016). trough concentration of voriconazole and its relationship with efficacy and safety: A systematic review and meta-analysis. J. Antimicrob. Chemother. 71 (7), 1772–1785. 10.1093/jac/dkw045 [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Klein M., Thomas M., Hofmann U., Seehofer D., Damm G., Zanger U. M. (2015). A systematic comparison of the impact of inflammatory signaling on absorption, distribution, metabolism, and excretion gene expression and activity in primary human hepatocytes and HepaRG cells. Drug Metab. Dispos. 43 (2), 273–283. 10.1124/dmd.114.060962 [DOI] [PubMed] [Google Scholar]
  16. Li A. P., Yang Q., Vermet H., Raoust N., Klieber S., Fabre G. (2014). Evaluation of human hepatocytes under prolonged culture in a novel medium for the maintenance of hepatic differentiation: Results with the model pro-inflammatory cytokine interleukin 6. Drug Metab. Lett. 8 (1), 12–18. 10.2174/187231280801140929155351 [DOI] [PubMed] [Google Scholar]
  17. Liang Z., Yu M., Liu Z., Liu F., Jia C., Xiong L., et al. (2022). Inflammation affects liver function and the metabolism of voriconazole to voriconazole-N-oxide in adult and elderly patients. Front. Pharmacol. 13, 835871. 10.3389/fphar.2022.835871 [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Manne B. K., Xiang S. C., Rondina M. T. (2017). Platelet secretion in inflammatory and infectious diseases. Platelets 28 (2), 155–164. 10.1080/09537104.2016.1240766 [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Matthaiou D. K., Dimopoulos G., Taccone F. S., Bulpa P., Van den Abeele A. M., Misset B., et al. (2018). Elderly versus nonelderly patients with invasive aspergillosis in the ICU: A comparison and risk factor analysis for mortality from the aspICU cohort. Med. Mycol. 56 (6), 668–678. 10.1093/mmy/myx117 [DOI] [PubMed] [Google Scholar]
  20. Moriyama B., Obeng A. O., Barbarino J., Penzak S. R., Henning S. A., Scott S. A., et al. (2017). Clinical pharmacogenetics implementation consortium (CPIC) guidelines for CYP2C19 and voriconazole therapy. Clin. Pharmacol. Ther. 102 (1), 45–51. 10.1002/cpt.583 [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Mosedale M., Watkins P. B. (2017). Drug-induced liver injury: Advances in mechanistic understanding that will inform risk management. Clin. Pharmacol. Ther. 101 (4), 469–480. 10.1002/cpt.564 [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Nicolai L., Massberg S. (2020). Platelets as key players in inflammation and infection. Curr. Opin. Hematol. 27 (1), 34–40. 10.1097/MOH.0000000000000551 [DOI] [PubMed] [Google Scholar]
  23. Niioka T., Fujishima N., Abumiya M., Yamashita T., Ubukawa K., Nara M., et al. (2017). Relationship between the CYP2C19 phenotype using the voriconazole-to-voriconazole N-oxide plasma concentration ratio and demographic and clinical characteristics of Japanese patients with different CYP2C19 genotypes. Ther. Drug Monit. 39 (5), 514–521. 10.1097/FTD.0000000000000441 [DOI] [PubMed] [Google Scholar]
  24. Portier I., Campbell R. A. (2021). Role of platelets in detection and regulation of infection. Arterioscler. Thromb. Vasc. Biol. 41 (1), 70–78. 10.1161/ATVBAHA.120.314645 [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Purkins L., Wood N., Ghahramani P., Greenhalgh K., Allen M. J., Kleinermans D. (2002). Pharmacokinetics and safety of voriconazole following intravenous-to oral-dose escalation regimens. Antimicrob. Agents Chemother. 46 (8), 2546–2553. 10.1128/AAC.46.8.2546-2553.2002 [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Shang S., Cheng L., Li X., Xiang R., Yu M., Xiong L., et al. (2020). Effect of CYP2C19 polymorphism on the plasma voriconazole concentration and voriconazole-to-voriconazole-N-oxide concentration ratio in elderly patients. Mycoses 63 (11), 1181–1190. 10.1111/myc.13105 [DOI] [PubMed] [Google Scholar]
  27. Tang D., Song B. L., Yan M., Zou J. J., Zhang M., Zhou H. Y., et al. (2019). Identifying factors affecting the pharmacokinetics of voriconazole in patients with liver dysfunction: A population pharmacokinetic approach. Basic Clin. Pharmacol. Toxicol. 125 (1), 34–43. 10.1111/bcpt.13208 [DOI] [PubMed] [Google Scholar]
  28. Tang D., Yan M., Song B. L., Zhao Y. C., Xiao Y. W., Wang F., et al. (2021). Population pharmacokinetics, safety and dosing optimization of voriconazole in patients with liver dysfunction: A prospective observational study. Br. J. Clin. Pharmacol. 87 (4), 1890–1902. 10.1111/bcp.14578 [DOI] [PubMed] [Google Scholar]
  29. Theuretzbacher U., Ihle F., Derendorf H. (2006). Pharmacokinetic/pharmacodynamic profile of voriconazole. Clin. Pharmacokinet. 45 (7), 649–663. 10.2165/00003088-200645070-00002 [DOI] [PubMed] [Google Scholar]
  30. Tsay S. V., Mu Y., Williams S., Epson E., Nadle J., Bamberg W. M., et al. (2020). Burden of candidemia in the United States, 2017. Clin. Infect. Dis. 71 (9), e449–e453. 10.1093/cid/ciaa193 [DOI] [PubMed] [Google Scholar]
  31. Ullmann A. J., Aguado J. M., Arikan-Akdagli S., Denning D. W., Groll A. H., Lagrou K., et al. (2018). Diagnosis and management of Aspergillus diseases: Executive summary of the 2017 ESCMID-ECMM-ERS guideline. Clin. Microbiol. Infect. 24 (1), e1–e38. 10.1016/j.cmi.2018.01.002 [DOI] [PubMed] [Google Scholar]
  32. Vallabhaneni S., Benedict K., Derado G., Mody R. K. (2017). Trends in hospitalizations related to invasive aspergillosis and mucormycosis in the United States, 2000-2013. Open Forum Infect. Dis. 4 (1), ofw268. 10.1093/ofid/ofw268 [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Vanstraelen K., Wauters J., Vercammen I., de Loor H., Maertens J., Lagrou K., et al. (2014). Impact of hypoalbuminemia on voriconazole pharmacokinetics in critically ill adult patients. Antimicrob. Agents Chemother. 58 (11), 6782–6789. 10.1128/AAC.03641-14 [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Veringa A., Ter Avest M., Span L. F., van den Heuvel E. R., Touw D. J., Zijlstra J. G., et al. (2017). Voriconazole metabolism is influenced by severe inflammation: A prospective study. J. Antimicrob. Chemother. 72 (1), 261–267. 10.1093/jac/dkw349 [DOI] [PubMed] [Google Scholar]
  35. Vreugdenhil B., van der Velden W., Feuth T., Kox M., Pickkers P., van de Veerdonk F. L., et al. (2018). Moderate correlation between systemic IL-6 responses and CRP with trough concentrations of voriconazole. Br. J. Clin. Pharmacol. 84 (9), 1980–1988. 10.1111/bcp.13627 [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Yan M., Wu Z. F., Tang D., Wang F., Xiao Y. W., Xu P., et al. (2018). The impact of proton pump inhibitors on the pharmacokinetics of voriconazole in vitro and in vivo . Biomed. Pharmacother. 108, 60–64. 10.1016/j.biopha.2018.08.121 [DOI] [PubMed] [Google Scholar]
  37. Yasu T., Konuma T., Kuroda S., Takahashi S., Tojo A. (2018). Effect of cumulative intravenous voriconazole dose on renal function in hematological patients. Antimicrob. Agents Chemother. 62 (9), e00507–e00518. 10.1128/AAC.00507-18 [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Zeng G., Wang L., Shi L., Li H., Zhu M., Luo J., et al. (2020). Variability of voriconazole concentrations in patients with hematopoietic stem cell transplantation and hematological malignancies: Influence of loading dose, procalcitonin, and pregnane X receptor polymorphisms. Eur. J. Clin. Pharmacol. 76 (4), 515–523. 10.1007/s00228-020-02831-1 [DOI] [PubMed] [Google Scholar]
  39. Zhao Y. C., Lin X. B., Zhang B. K., Xiao Y. W., Xu P., Wang F., et al. (2021b). Predictors of adverse events and determinants of the voriconazole trough concentration in kidney transplantation recipients. Clin. Transl. Sci. 14 (2), 702–711. 10.1111/cts.12932 [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Zhao Y., Xiao C., Hou J., Wu J., Xiao Y., Zhang B., et al. (2021a). A large sample retrospective study on the distinction of voriconazole concentration in asian patients from different clinical departments. Pharm. (Basel) 14 (12), 1239. 10.3390/ph14121239 [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Zhou Z. X., Yin X. D., Zhang Y., Shao Q. H., Mao X. Y., Hu W. J., et al. (2022). Antifungal drugs and drug-induced liver injury: A real-world study leveraging the fda adverse event reporting System database. Front. Pharmacol. 13, 891336. 10.3389/fphar.2022.891336 [DOI] [PMC free article] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Data Availability Statement

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

Articles from Frontiers in Pharmacology are provided here courtesy of Frontiers Media SA

RESOURCES