Invasive fungal infections (IFIs) are opportunistic infections with high mortality rates that occur primarily in immunocompromised patients, especially in those with hematological diseases (Wang et al., 2019). Voriconazole (VRC), a broad-spectrum triazole antifungal agent, is the first-line treatment for the prevention and management of IFIs (Patterson et al., 2016). Given its nonlinear pharmacokinetics and high inter- and intra-individual variability, therapeutic drug monitoring (TDM) is essential. Adverse drug reactions (ADRs) associated with VRC, including hepatotoxicity, visual disturbances, and hallucinations, have been correlated with elevated trough concentrations (C _trough) (Hanai et al., 2021; Jin et al., 2016). Therefore, individualized VRC dosing is critical to optimizing therapeutic efficacy while minimizing the risk of toxicity.

VRC is primarily metabolized in the liver by the cytochrome P450 2C19 (CYP2C19) enzyme (Weiss et al., 2009). CYP2C19 exhibits genetic polymorphisms, with allelic variants such as *2, *3, and *17 contributing to interindividual differences in metabolic capacity. According to the Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines (CPIC, 2018), the distribution of CYP2C19 phenotypes varies between Asian and Caucasian populations, potentially affecting optimal VRC dosing. The 2022 Japanese Society of Chemotherapy and the Japanese Society of Therapeutic Drug Monitoring (JSC/JSTDM) consensus (Takesue et al., 2022) recommends population-specific VRC dosing strategies for Asians and non-Asians to minimize the risk of overdose. Beyond genetic variation, our previous research has also identified non-genetic factors—including age, concomitant medications, and liver function, as significant contributors to variability in VRC C _trough (Hu et al., 2024a).

Our recent research demonstrated a significant correlation between VRC C _trough and Child-Pugh (CP) classification in patients with hepatic dysfunction (Hu et al., 2024b). Similarly, a population pharmacokinetic (PPK) study by Tang et al. identified a significant association between VRC clearance (CL) and total bilirubin (TBIL) levels (Tang et al., 2021). In clinical practice, VRC dosing is frequently adjusted based on the patient’s liver function. While the CP classification remains the most commonly used tool for liver function assessment, recent studies (Nashimoto et al., 2023; Asai et al., 2025) have suggested that the albumin-bilirubin (ALBI) grade may also correlate with VRC C _trough and could aid in optimizing initial dosing and predicting hepatotoxicity. The ALBI grade is calculated using two readily accessible biomarkers—serum albumin (ALB) and TBIL, both of which are obtained through routine blood tests.

Therefore, this study retrospectively collected clinical data from patients who had simultaneous measurements of steady-state VRC C _trough and CYP2C19 genotypes. Liver function was assessed using the ALBI grade. The primary objective of this study was to evaluate the influence of both genetic and non-genetic factors on VRC C _trough. In addition, the study assessed the efficacy and safety of VRC in Chinese hematological patients, providing a scientific basis for the individualized use of VRC in this population.

This study evaluated the impact of both CYP2C19 genetic polymorphisms and non-genetic factors, including ALBI grade, on VRC C _trough in Chinese patients. It also investigated the VRC dosing required to achieve the target therapeutic range and described dose adjustments, efficacy, and safety within the study population.

Significant differences in VRC C _trough were observed among the three CYP2C19 phenotypes. In this study, PMs exhibited significantly higher VRC C _trough than NMs and IMs, were consistent with our previous studies (Hu et al., 2023a; Hu et al., 2023b). CYP2C19 phenotype has been shown to effectively guide initial VRC dosing and is often used to explain subtherapeutic concentrations (Zonios et al., 2014). NMs are less likely to present with subtherapeutic VRC levels. Our study demonstrated that patients with VRC concentrations < 1.0 mg/L exhibited poor treatment responses, aligning with findings by Pascual et al., who also reported that low VRC levels were associated with reduced therapeutic efficacy (Pascual et al., 2008). Treatment success significantly improves when the C _trough is ≥ 1.0 mg/L (Hanai et al., 2021). Therefore, the VRC dose in NMs should be appropriately increased to enhance the likelihood of achieving therapeutic levels and improving treatment efficacy. The CPIC guidelines (CPIC, 2018) recommended using CYP2C19 genotyping to inform VRC dosing strategies. Standard dosing is advised for NMs and IMs. For PMs, alternative antifungal agents not primarily metabolized by CYP2C19 are preferred. However, if VRC remains the most appropriate option, a reduced dose in combination with TDM is recommended.

Numerous pharmacogenomic studies have demonstrated that the CYP2C19 PMs has the highest prevalence in East Asian populations (approximately 13%–23%), which is substantially higher than in Caucasian populations (approximately 1%–6%) (Desta et al., 2002; Zhou et al., 2019; Lamoureux et al., 2016; Zonios et al., 2014). In our study, CYP2C19 PMs accounted for 13.5% of the cohort, a frequency consistent with previous reports. Consequently, patients with hematologic diseases in Asian populations may have an inherently higher risk of VRC overexposure and related toxicity compared with populations where the PMs is less frequent. Given the higher prevalence of PMs in Asian populations, a reduced maintenance dose may be necessary to attain comparable C _trough. Due to genetic differences, the manufacturer’s original dosing recommendations (Pfizer Limited, 2012) may not be optimal for Chinese patients. The 2022 JSC/JSTDM Consensus (Takesue et al., 2022) recommended a maintenance dose of 3 mg/kg for Asian patients, considering the tendency for elevated C _trough levels and a higher incidence of ADRs.

Our findings underscore not only the universal importance of individualized VRC therapy but also its particular relevance in Asian populations. When extrapolating our results to other ethnic groups, the distribution of CYP2C19 genotypes in the target population must be carefully considered. For instance, in populations where the PMs is rare, other factors, such as drug–drug interactions and hepatic function, may play a comparatively greater role. Conversely, our data provide region-specific evidence supporting the implementation of CYP2C19 genotype-guided dosing strategies in Asian medical centers. Future multicenter, multiethnic studies are warranted to establish more generalizable models that can accurately quantify the combined effects of genotype, ethnicity, and clinical factors on VRC pharmacokinetics.

In this study, only CYP2C19 genetic polymorphisms were analyzed, while other enzymes and transporters that may also affect VRC metabolism were not evaluated. He et al. provided novel insights into the role of CYP3A4 in VRC pharmacokinetics (He et al., 2015). Similarly, Gautier-Veyret et al. (2016) demonstrated that a combined genetic score incorporating CYP2C19 and CYP3A4 genotypes could predict VRC C _trough. However, other studies have reported inconsistent findings. For instance, no significant associations were observed between CYP3A4, ABCB1, or FMO3 genotypes and plasma VRC C _trough (Chuwongwattana et al., 2020). Furthermore, while several studies recommended CYP2C19 genotyping to optimize VRC dosing in patients, research in healthy Chinese adults suggested that polymorphisms in CYP2C9, CYP3A4, and FMO3 may have minimal impact on VRC pharmacokinetics (Liu et al., 2024).

Li et al. (2017) demonstrated that liver function and CYP2C19 polymorphisms are major determinants of VRC pharmacokinetic variability, a conclusion consistent with our findings. In our previous research, we also identified that ALB, alanine aminotransferase, and direct bilirubin levels significantly influence VRC C _trough (Hu et al., 2024b; Hu et al., 2023b). Accordingly, in this study, we adopted the ALBI grade to assess liver function instead of the CP classification. Unlike the CP system, which incorporates subjective factors such as ascites and hepatic encephalopathy, the ALBI grade offers a more objective and precise evaluation of liver function and is applicable to patients with both cirrhotic and non-cirrhotic liver diseases. Therefore, using ALBI grading to assess liver function for guiding VRC dosing may offer a more broadly applicable alternative to the CP classification. The recent PPK study of VRC in patients with hepatic dysfunction evaluated optimal dosing based on ALBI grading. The recommended regimens were 100 mg twice daily, 75 mg twice daily, and 50 mg twice daily for ALBI scores of −3, −2, and −1, respectively (Nashimoto et al., 2025).

Our previously published studies (Hu et al., 2018) demonstrated that VRC C _trough following intravenous administration were significantly higher than those observed after oral administration in pediatric patients. Similar findings were observed in the present cohort. A potential explanation is that VRC absorption differs between children and adults. The oral bioavailability of VRC in children is approximately 44% (Purkins et al., 2002), compared to over 90% in adults (Veringa et al., 2017) (the present study included patients as young as 15 years). Additionally, oral administration is more susceptible to first-pass metabolism and drug–drug interactions. Intestinal CYP3A4 also serves as a barrier to VRC absorption. Moreover, oral VRC absorption may be influenced by factors such as concurrent food intake, gastrointestinal complications, and diarrhea.

Allegra et al. (2018) reported that males had significantly higher median VRC C _trough than females and that C _trough was positively correlated with age. Similarly, Hashemizadeh et al. (2017) found that reduced VRC concentrations were associated with the concomitant use of glucocorticoids. These findings are consistent with the results of our study. In this study, 16.9% of patients received VRC via intravenous administration. The intravenous formulation contains sulfobutyl ether-β-cyclodextrin (SBECD), which is normally eliminated through the kidneys but may accumulate in patients with renal impairment, potentially leading to nephrotoxicity. At high cumulative doses (≥400 mg/kg), SBECD accumulation may further exacerbate renal dysfunction (Yasu et al., 2018). Dolton et al. (2014) proposed that glucocorticoids may induce cytochrome P450 enzymes, particularly CYP enzymes, thereby enhancing VRC metabolism and reducing its plasma concentration. Several studies have also examined the impact of PPIs on VRC C _trough. For instance, Yan et al. (2018) reported that co-administration of omeprazole significantly increased VRC plasma levels. Hashemizadeh et al. (2017) similarly observed elevated VRC concentrations with the co-administration of omeprazole or pantoprazole. However, in our study, the concomitant use of PPIs did not have a statistically significant effect on VRC C _trough. A possible explanation is that most patients in our cohort were co-administered pantoprazole or lansoprazole, which exert less inhibitory effect on CYP2C19 compared to omeprazole.

Although CYP2C19 polymorphisms significantly influence VRC C _trough, relying solely on CYP2C19 genotyping is insufficient for accurately guiding VRC dose optimization. Therefore, it is essential to integrate nonlinear pharmacokinetics, CYP2C19 genotyping, and other non-genetic factors when determining initial VRC dosing. Dose adjustments should subsequently be guided by TDM. Significant non-genetic factors identified in this study, such as ALBI grade and concomitant use of glucocorticoids, Ccr should be considered in future prospective PPK studies. Only 10 patients in our study underwent dose adjustments based on TDM, which limits the strength of conclusions regarding the effectiveness of TDM-guided interventions. However, evidence from previous studies suggested that earlier implementation of TDM may improve outcomes. For instance, Shen et al. (2022) reported that VRC-induced hepatotoxicity occurred in 66.7% of patients within 7 days of the first dose and in 94.4% within 15 days. Hu et al. (2024b) reported that the median time to onset of ADRs after initiating VRC therapy was 7.5 days. These findings underscore the potential of early TDM to substantially improve clinical outcomes. The Chinese Pharmacological Society (CPS) guidelines (Chen et al., 2018) recommended increasing the maintenance dose of VRC by 50% if C _trough is < 1.0 mg/L or if treatment efficacy is inadequate. If the C _trough is between 5 and 10 mg/L without CTCAE grade 2 or higher adverse events, a 20% dose reduction is advised. If the C _trough > 10 mg/L or if CTCAE grade 2 or higher adverse events occur, VRC administration should be interrupted, followed by a 50% reduction in the maintenance dose upon resumption.

Recent researches have demonstrated that CRP, a biomarker of inflammation, is significantly correlated with VRC C _trough (Hu et al., 2025; Encalada Ventura et al., 2016). Inflammatory status may reduce VRC metabolism, leading to elevated VRC C _trough. Specifically, for every 1 mg/L increased in CRP, VRC C _trough increased by approximately 0.015 mg/L (van Wanrooy et al., 2014). The risk of VRC overexposure and associated adverse reactions rised markedly in patients with CRP levels >102.23 mg/L (Lin et al., 2023). Furthermore, PPK studies have identified CRP as a significant covariate influencing the maximum enzymatic activity (V_max) (van den Born et al., 2023). Consistently, Ling et al. (2024) reported that CRP is an important covariate affecting VRC clearance. However, our study did not include CRP concentration, preventing us from evaluating the impact of inflammatory factors on VRC C _trough. Future large-scale prospective studies are warranted to investigate the optimal VRC dosing strategies based on CRP stratification.

The intrinsic characteristics of malignancy, such as disease type, stage, activity, and degree of inflammation, may indirectly affect VRC C _trough by altering systemic physiological conditions, including inflammatory cytokine levels, serum protein concentrations, and liver function. These factors may therefore serve as potential unmeasured confounders. However, due to the retrospective nature of our study, specific biomarkers and detailed baseline disease status could not be obtained. Malignancy status represents an incompletely measured confounding factor, which should be addressed in the design of future studies.

CYP2C19 phenotype, ALBI grade, sex, Ccr and concomitant use of glucocorticoids were identified as significant contributors to the variability of VRC C _trough/D and should be comprehensively considered when determining appropriate VRC dosing. Compared with the CP classification, ALBI grading may offer broader applicability for guiding individualized VRC therapy. Future PPK studies should incorporate these factors to establish more precise and personalized dosing strategies. Additionally, investigating VRC dose adjustment strategies in special populations, such as pediatric patients, individuals with hepatic impairment, or organ transplant recipients—is of particular importance due to limited existing data. Future research should prioritize these populations to enhance the efficacy and safety of VRC use.