Real-world study of posaconazole tablets for the prophylaxis of invasive fungal disease in patients with end-stage liver disease

Abstract

Background

Data on the pharmacokinetics and tolerability of posaconazole delayed-release tablets in patients with end-stage liver disease (ESLD)(including liver failure and decompensated cirrhosis) remain limited. This study aimed to characterize trough concentrations (Cmin) and describe clinical outcomes during antifungal prophylaxis in this population.

Methods

In this prospective, single-arm study, ESLD patients receiving posaconazole prophylaxis were enrolled between October 2023 and July 2024. Serial Cmin were measured, and hepatic and renal function parameters were monitored. Breakthrough invasive fungal disease (IFD) events were descriptively recorded.

Results

Twenty-one patients contributed 79 Cmin measurements. The mean Cmin was 1.60 ± 0.68 mg/L, with 81.0% of samples ≥ 1.0 mg/L; 95.2% of patients achieved at least one target concentration. Substantial interindividual variability was observed, while dose adjustments were infrequent. Breakthrough IFD occurred in 2 patients (9.5%), with no IFD-related deaths. Liver and renal function parameters remained generally stable during follow-up. Reductions in total bilirubin were observed in patients with more advanced liver dysfunction (Model for End-Stage Liver Disease (MELD) > 18 or Child–Pugh C), although these changes were not attributable to posaconazole.

Conclusion

Posaconazole exposure in patients with ESLD showed considerable interindividual variability, despite most Cmin measurements were within the predefined reference range of 0.5-2.5 mg/L. The drug was generally well tolerated in this cohort. These findings support the role of therapeutic drug monitoring (TDM) in characterizing exposure variability in ESLD. Given the small sample size and observational design, the results are descriptive, and further studies are needed to define optimal dosing and monitoring strategies in this high-risk population.

Trial registration

ChiCTR2200063000. Registration on 27 August 2022.

Supplementary Information

The online version contains supplementary material available at https://doi.org/10.1186/s12876-026-05131-7.

Background

End-stage liver disease (ESLD) broadly refers to advanced liver disease with varying severity, including conditions such as liver failure and decompensated cirrhosis. Patients with ESLD often have significant immune dysfunction together with multiple comorbidities, which may increase their susceptibility to infections [1]. In clinical practice, those with severe disease or multi-organ involvement are generally considered at higher risk for opportunistic infections.

Recent studies have suggested that invasive fungal disease (IFD) is increasingly observed in patients with ESLD, with Candida and Aspergillus being the most frequently reported pathogens [2]. The diagnosis of IFD in this population can be difficult because symptoms are often nonspecific, and treatment options may be limited due to impaired liver function. Reported incidence rates vary from 2% to 15%, and mortality remains high, exceeding 45% in some reports [3–5].

However, evidence regarding antifungal prophylaxis in patients with ESLD is still limited, and there is no clear consensus on its use in this setting. Posaconazole is a broad-spectrum triazole antifungal agent that is commonly used for prophylaxis in selected high-risk populations. The oral suspension formulation has variable absorption, which can be affected by food intake and gastrointestinal function—both of which are frequently altered in ESLD. In comparison, the delayed-release tablet formulation provides more stable drug exposure and is less influenced by gastric pH, food intake, or proton pump inhibitor use [6]. Nevertheless, data on the pharmacokinetics and tolerability of posaconazole delayed-release tablets in patients with ESLD remain scarce.

In this context, we conducted this study to describe trough concentration (Cmin) profiles and evaluate the tolerability of posaconazole delayed-release tablets in patients with ESLD. The aim was to provide descriptive pharmacokinetic and safety data to better characterize drug exposure in this population.

Methods

Patients

This was a prospective, open‑label, single‑arm observational study conducted at the Department of Infectious Diseases, The First Affiliated Hospital of Xi’an Jiaotong University, between April 2023 and July 2024. The study was designed to describe posaconazole exposure and evaluate its tolerability in patients with ESLD receiving antifungal prophylaxis. A total of 21 patients with ESLD who received posaconazole delayed-release tablets for prophylaxis against IFD were enrolled.

The study protocol was approved by the Ethics Committee of The First Affiliated Hospital of Xi’an Jiaotong University (Approval No. XJTU1AF2019LSK‑071) and registered in the Chinese Clinical Trial Registry (ChiCTR2200063000, Registration Date 2022/08/27). Written informed consent was obtained from all participants prior to study inclusion. For participants under the age of 16 years, written informed consent to participate was obtained from their parents or legal guardians.

Patients were eligible if they provided written informed consent, were aged ≥ 13 years, and had advanced liver disease consistent with ESLD. ESLD was operationally defined as a heterogeneous condition including patients with liver failure (e.g., acute liver failure (ALF), subacute liver failure (SALF), or acute-on-chronic liver failure (ACLF)) as well as those with decompensated cirrhosis.

For patients with liver failure, diagnosis was established according to the Chinese Guidelines [7], based on clinical manifestations such as fatigue, gastrointestinal symptoms, marked elevation of alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST), progressive jaundice (total bilirubin (TBIL) 85.5–170.9 µmol/L or daily increase ≥ 17.1 µmol/L), and coagulation dysfunction(prothrombin activity 40% -50%, corresponding to international normalized ratio (INR) < 1.5), together with moderate-to-severe hepatic impairment as assessed by the Child–Pugh score. Patients with decompensated cirrhosis without liver failure were also eligible in this real-world observational study. All patients included received posaconazole delayed-release tablets for antifungal prophylaxis and had at least two available Cmin measurements. Female patients of childbearing potential were required to use effective contraception or have no risk of pregnancy.

Exclusion criteria included known hypersensitivity to posaconazole, inability to tolerate oral intake, pregnancy or breastfeeding, expected survival of less than 72 h, lack of informed consent, a history of substance or alcohol abuse, or any condition that, in the investigator’s judgment, could interfere with study assessments or pose an unacceptable risk.

IFD prophylaxis regimen

Posaconazole delayed‑release tablets were administered according to the approved prescribing information, with a loading dose of 300 mg twice daily on day 1, followed by a maintenance dose of 300 mg once daily from day 2 onward. Cmin was generally obtained at predefined time points (days 3, 5, 7, 10, and 14) after initiation. In practice, sampling times could vary depending on the clinical condition and feasibility, and dosing decisions were guided by therapeutic drug monitoring (TDM) in routine care. Therefore, all available Cmin measurements obtained during the observation period were included in the descriptive analysis, while predefined and clinically indicated sampling time points were distinguished where relevant.

A predefined reference Cmin range of 0.5–2.5 mg/L was used as a reference for interpretation. The lower threshold (0.5 mg/L) was based on commonly reported exposure targets in the literature [8], while the upper limit (2.5 mg/L) was derived from exposure ranges observed in phase III studies [9]. As no clear exposure–toxicity threshold has been established for posaconazole, this upper limit was considered a pragmatic reference rather than a definitive safety cutoff. Accordingly, measured Cmin values were categorized as below the reference range (< 0.5 mg/L), within the reference range (0.5–2.5 mg/L), or above the reference range (≥ 2.5 mg/L).

When Cmin outside the target range were observed, potential contributing factors-such as drug-drug interactions, gastrointestinal dysfunction, or adherence issues—were first considered. In such cases, dosing was not routinely adjusted, and repeat TDM was performed when appropriate. Similarly, if sampling conditions were considered suboptimal (e.g., non-steady-state sampling or uncertain timing), the results were interpreted with caution, and repeat measurements were obtained.

Dose adjustments were considered on an individual basis when no clear clinical or technical explanation for abnormal exposure was identified. In general, dose escalation (e.g., to 400 mg daily) could be considered for patients with Cmin values below the reference range (< 0.5 mg/L), with close monitoring. Conversely, dose reduction (e.g., to 200 mg once daily) could be considered for patients with elevated exposure(≥ 2.5 mg/L) as a precautionary measure to avoid excessive exposure.

Endpoints

The primary endpoint was the distribution of posaconazole Cmin across all available sampling time points during the observation period. Predefined sampling time points included days 3, 5, 7, 10, and 14 after treatment initiation; however, additional clinically indicated TDM measurements were also included in the analysis. In addition, Cmin values observed in patients who underwent dose adjustment were descriptively summarized. Secondary endpoints included: changes in hepatic and renal function parameters during prophylaxis, drug tolerability, the incidence of breakthrough IFD during hospitalization, and other clinical events.

Definitions

IFD was defined according to the updated European Organization for Research and Treatment of Cancer / Mycoses Study Group Education and Research Consortium (EORTC/MSGERC) consensus criteria [10] and categorized as proven, probable, or possible IFD based on host factors, clinical features, and mycological evidence, in accordance with the EORTC/MSGERC definitions. Breakthrough IFD was defined as proven or probable IFD occurring during posaconazole exposure. Infections developing after at least 5 days of posaconazole administration were considered breakthrough events. Clinical outcomes were categorized as either no breakthrough infection or breakthrough IFI. For patients who developed IFD, subsequent management and clinical course were descriptively recorded. Child–Pugh classification and Model for End-Stage Liver Disease (MELD) scores were calculated using established criteria [11–12].

Therapeutic drug monitoring

Posaconazole Cmin were measured using a validated high-performance liquid chromatography–tandem mass spectrometry (HPLC–MS/MS) assay (Thermo Fisher Scientific Ultimate™ 3000 system coupled with a triple quadrupole (TSQ) Vantage triple quadrupole mass spectrometer). The assay was developed based on previously published methods [13] and validated for specificity, linearity, accuracy, precision, recovery, matrix effects, and stability. The calibration range was 0.02–12 mg/L. All measured concentrations fell within the validated calibration range; therefore, no samples required dilution before quantification. Venous blood samples (2 mL) were collected in ethylenediaminetetraacetic acid (EDTA) tubes and processed within standard laboratory procedures. Plasma was separated by centrifugation at 4 °C (3000 rpm for 10 min) and stored at − 80 °C until analysis.

Cmin were generally collected at predefined time points. However, as this was an observational study, sampling was performed as part of routine clinical care rather than under a strictly controlled protocol. As a result, not all patients had measurements at each predefined time point due to clinical and logistical reasons (e.g., patient instability, early discharge, or missed sampling). Additional samples were obtained at the discretion of the treating physicians when clinically indicated.

All available concentration data, including those collected outside predefined time points, were included in the analysis to reflect real-world practice and minimize potential selection bias.

Quality control criteria required that at least two-thirds of quality control samples at each level were within ± 15% of nominal values (± 20% at the lower limit of quantification). Analytical runs not meeting these criteria were excluded.

Statistical analysis

All statistical analyses were performed using SPSS software (version 32). Continuous variables were summarized using descriptive statistics, including mean with standard deviation (SD) or median with range, as appropriate. Categorical variables were presented as counts and percentages.

Given the exploratory and descriptive nature of the study, formal hypothesis testing was interpreted with caution. For paired comparisons before and after posaconazole prophylaxis, paired t-tests were used when data were approximately normally distributed; otherwise, the Wilcoxon signed-rank test was applied.

Changes in liver and renal function parameters were evaluated by calculating the difference between post-treatment and baseline values (Δ = post-treatment − baseline), which were summarized descriptively. Linear mixed-effects models were used to explore changes in Cmin over time, taking into account repeated measurements within individuals.

Subgroup analyses according to MELD score categories and Child–Pugh classification were performed as exploratory analyses using the same statistical approach. All tests were two-sided, and a P value < 0.05 was considered nominally significant.

For the exploratory analysis of the relationship between concomitant medications and posaconazole exposure, only pre-dose-adjustment Cmin measurements were included to minimize the potential influence of TDM-guided dose modification. Post-dose-adjustment Cmin values were excluded from this analysis. Given the limited sample size, this analysis was considered descriptive and exploratory.

Result

Patient characteristics

A total of 21 patients with ESLD received posaconazole prophylaxis for at least 3 days during hospitalization. The cohort included patients with varying degrees of liver dysfunction, including both liver failure and decompensated cirrhosis. Their baseline characteristics are summarized in Table 1. The cohort comprised 17 men and 4 women, with a mean age of 55.52 ± 14.36 years. 16 patients had liver failure, of whom 6 also had decompensated cirrhosis. The remaining 5 patients had decompensated cirrhosis without liver failure. Concomitant medications that may influence posaconazole exposure or infection risk were commonly used, including proton pump inhibitors (61.9%), corticosteroids (14.3%), broad-spectrum antibiotics (9.5%), and immunosuppressive agents (28.6%). In exploratory analyse restricted to pre-dose-adjustment Cmin measurements, no clear association was observed between these co-administered medications and posaconazole Cmin (all P > 0.05, Supplementary Table S1).

Table 1.

Baseline characteristics of the study population, including concomitant medications

Demographice	N (%)
Gender, female: male	4:17
Age(yr)	55.52 ± 14.36
Causes of liver disease, n(%) of patients
Chronic hepatitis B	23.8%(5)
Alcoholic	19.0%(4)
Autoimmune diseases	23.8%(5)
Drug-induce liver injury	19.0%(4)
Cryptogenic	9.6%(2)
Hepatocellular carcinoma	4.8%(1)
Classification of liver disease status
ALF	4.8%(1)
SALF	19.0%(4)
ACLF	42.9%(9)
Type I	66.7%(6/9)
Type II	33.3%(3/9)
CLF	9.5%(2)
Decompensated cirrhosis without liver failure	23.8%(5)
Baseline laboratory findings
Absolute Neutrophil Count(10^9/L)	5.89 ± 7.56
ALT(U/L)	65.76 ± 108.34
AST(U/L)	97.28 ± 181.14
TBIL(µmol/L)	163.99 ± 139.41
TP (g/L)	60.48 ± 32.70
ALB (g/L)	31.09 ± 4.86
CRE (µmol/L)	86.70 ± 53.95
INR	1.77 ± 0.64
Evaluation of liver function
Child Pugh Class, B:C	9:12
MELD score	16.37 ± 7.25
Concomitant Medication
Proton pump inhibitors	61.9% (13/21)
Corticosteroids	14.3% (3/21)
Broad-spectrum antibiotics	9.5% (2/21)
Immunosuppressive agents	28.6% (6/21)
Treatment
Duration(days)	19.69 ± 6.87
Dose adjustment (%)	10.1%(8/79)
Average time to dose adjustment (days)	9.86 ± 4.38

ALF Acute liver failure, SALF Subacute liver failure, ACLF Acute-on-chronic liver failure, CLF Chronic liver failure, ALT Alanine aminotransferase, AST Aspartate aminotransferase, TBIL Total bilirubin, TP Total Protein, ALB Albumin, CRE Serum creatinine, INR International normalized ratio, MELD Model for end-stage liver disease

All patients underwent Child–Pugh classification and MELD score assessment prior to treatment initiation. Nine patients were classified as Child–Pugh class B and twelve as class C, with a mean MELD score of 16.37 ± 7.25. Hepatic encephalopathy was present in eight patients, including four with grade I–II and four with grade III–IV. Ascites was observed in 15 patients ( seven mild and eight moderate-to-severe). In terms of disease severity, 10 patients had MELD scores > 18, two had scores between 15 and 18, and nine had scores < 15.

Liver function classification and clinical events

Liver function status and clinical outcomes of the 21 enrolled patients were summarized in Table 2. Among the nine patients with ACLF, six were classified as type I (two in the pre‑stage, three in the early stage, and one in the middle stage), and three as type II (two in the early stage and one in the middle stage). During hospitalization, two patients (9.5%) developed possible breakthrough IFD. Their corresponding posaconazole Cmin and clinical details are presented in Table 3.

Table 2.

Baseline liver disease classification and clinical outcomes of the 21 patients

Causes of liver disease	Patient ID	Classification of liver function impairment	Clinical outcomes
Chronic hepatitis B	2	ACLF	Discharged with improved condition
	5, 6	ACLF, Decompensated liver cirrhosis	Discharged with improved condition
	10	ALF	Death
	4	Decompensated liver cirrhosis	Discharged with improved condition
Alcoholic	18	Decompensated liver cirrhosis	Change IFD treatment
	16, 19	ACLF, Decompensated liver cirrhosis	Discharged with improved condition
	1	SALF	Treatment abandonment
Autoimmune diseases	3, 7	CLF	Discharged with improved condition
	11	ACLF, Decompensated liver cirrhosis	Death
	15		Treatment abandonment
	21	SALF	Discharged with improved condition
Drug-induce liver injury	12	ACLF	Discharged with improved condition
	8	SALF	Prevention failure, death
	13		Discharged with improved condition
	14	Decompensated liver cirrhosis	Discharged with improved condition
Cryptogenic	17	Decompensated liver cirrhosis	Discharged with improved condition
	20	ACLF	Liver transplantation
Hepatocellular carcinoma	9	Decompensated liver cirrhosis	Discharged with stable condition

ACLF Acute-on-chronic liver failure, SALF Subacute liver failure, ALF Acute liver failure, CLF Chronic liver failure, IFD Invasive fungal disease

Table 3.

Cinical characteristics of Two patients with breakthrough IFD

ID	Patient No.8	Patient No.18
Underlying liver disease	Drug-induce liver injury	Alcoholic
clinical manifestations	Multiple pulmonary nodules	Large-volume ascites, intra-abdominal abscess
Microbiological findings	G positive (serum) / GM negative	G positive (serum and ascitic fluid) / GM negative
EORTC/MSGRC criteria	Probable IFD	Probable IFD
Mean Cmin (mg/L)	2.33	1.49
Timing of IFD	Day 10 after prophylaxis	Day 21 after prophylaxis
Antifungal management	Liposomal amphotericin B	Voriconazole
Outcome	Death due to underlying disease	Discharged with improved condition

EORTC/MSGRC European organization for research and treatment of cancer / mycoses study group education and research consortium, G Serum (1→3)-β-D-glucan, GM Serum galactomannan index, IFD Invasive fungal disease, Cmin Trough concentration

A total of three deaths, two treatment withdrawals, fifteen discharges, and one transfer for liver transplantation were recorded. The overall incidence of IFD was 9.5%. All deaths were related to progression of underlying liver disease.

Trough concentration monitoring

A total of 79 trough concentration measurements obtained across predefined and clinically indicated sampling time points were included in the analysis. The mean Cmin was 1.60 ± 0.68 mg/L, with a median interquartile range (IQR) of 1.54 mg/L (1.18–2.00).Using a predefined reference Cmin range of 0.5–2.5 mg/L, 84.8% (67/79) measurements were within the reference range, 5.1% (4/79) measurements were below 0.5 mg/L, and 10.1% (8/79) measurements were ≥ 2.5 mg/L. For comparison, when applying a commonly used target threshold of ≥ 1.0 mg/L [9], 81.0% (64/79) of measurements were met this threshold. when applying a threshold of ≥ 0.5 mg/L, the proportion increased to 94.9% (75/79).The distribution of Cmin across different time points is shown in Fig. 1, and detailed results are provided in Supplementary Table S2. Variability in Cmin was observed, particularly at earlier time points.

Fig. 1.

Distribution of posaconazole trough concentrations (Cmin) at different time points

At the patient level (n = 21), the mean Cmin was 1.51 mg/L (95% CI: 1.42–1.59), with a median (IQR) of 1.49 mg/L (0.97–1.79). As a patient-level supplementary analysis, using a threshold of ≥ 1.0 mg/L, 95.2% (20/21) of patients achieved at least one target concentration during the study period, and 61.9% (13/21) of patients maintained Cmin above this level at all measured time points. With a threshold of ≥ 0.5 mg/L, all patients achieved at least one concentration above this threshold, and 81.0% (17/21) of patients remained above this level across all available measurements. At the patient level, 10 patients had all available Cmin values within the reference range, 4 patients had at least one Cmin value below 0.5 mg/L, and 7 patients had at least one Cmin value ≥ 2.5 mg/L.

Dose adjustments were made in a limited number of cases. Dose reductions were recorded in 10.1% (8/79) measurements, and dose increases in 3.8% (3/79). Seven patients underwent dose reduction to 200 mg/day because of elevated Cmin values(Cmin ≥ 2.5 mg/L), while three patients received dose escalation because of low exposure (Cmin < 0.5 mg/L). Dose reductions were further described according to hepatic impairment severity. Dose reduction was required in 2 of 9 patients with Child–Pugh class B disease and in 5 of 12 patients with Child–Pugh class C disease. When stratified by MELD score, dose reduction was required in 3 of 11 patients with MELD scores ≤ 18 and in 4 of 10 patients with MELD scores > 18. Given the small sample size and the limited number of dose-reduction events, these findings were considered descriptive and no formal statistical comparison was performed.

Among patients who underwent dose reduction, median Cmin changed from 2.64 mg/L (IQR 2.01–3.08) before adjustment to 2.15 mg/L (IQR 1.62–2.42) on subsequent measurement. In patients requiring dose escalation, median Cmin changed from 0.44 mg/L (IQR 0.42–0.44) to 1.22 mg/L (IQR 0.78–1.25). The median interval between measurements was 6.57 days. After dose adjustment, 8 of 10 patients had subsequent Cmin within the predefined reference range of 0.5–2.5 mg/L. Overall, Cmin tended to be more variable in the early phase of treatment and appeared relatively stable at later time points.

Mean Cmin values were 1.68 ± 0.45 mg/L in Child–Pugh class C patients and 1.49 ± 0.47 mg/L in class B patients (P = 0.21). When stratified by MELD score, mean Cmin values were 1.44 ± 0.41 mg/L (≤ 14), 1.90 ± 0.37 mg/L (15–18), and 1.68 ± 0.50 mg/L (> 18) (P = 0.15). No clear differences in Cmin were observed across subgroups.

Figure 1. Distribution of posaconazole trough concentrations (Cmin) across sampling time points. Boxplots illustrate the median, interquartile range (IQR), and range of Cmin values at each sampling time point. The horizontal dashed lines represent target thresholds of 0.5 mg/L (lower limit) and 2.5 mg/L (primary target level). Outliers are shown as individual data points. Sampling was performed at predefined and clinically indicated time points.

Liver and renal function

Changes in liver and renal function parameters were evaluated relative to baseline. Analyses were stratified by Child–Pugh class (B vs. C). Given the limited sample size, MELD scores were dichotomized (≤ 18 vs. > 18) for comparison. Mean differences (Δ values; post-treatment minus baseline) are summarized as mean ± SD (Table 4).

Table 4.

Changes in hepatic and renal function parameters from baseline to during posaconazole prophylaxis stratified by MELD score

Variable	MELD≤18				MELD>18
	Baseline	Post-mean	Mean Diff	P value	Baseline	Post-mean	Mean Diff	P value
ALT	82.00 ± 103.29	69.52 ± 51.03	-12.48 ± 102.82	0.859	96.30 ± 158.30	61.82 ± 75.41	-34.48 ± 178.73	0.646
AST	105.91 ± 99.38	98.77 ± 104.02	-7.14 ± 131.64	0.657	123.30 ± 173.57	107.37 ± 120.57	-15.94 ± 227.56	0.878
TP	55.51 ± 10.25	54.91 ± 7.63	-0.60 ± 5.41	0.799	57.32 ± 7.54	67.25 ± 23.75	9.93 ± 27.63	0.308
ALB	28.18 ± 4.75	30.12 ± 4.20	1.93 ± 4.00	0.091	28.91 ± 4.40	32.09 ± 3.43	3.18 ± 4.79	0.114
TBIL	202.48 ± 148.50	164.61 ± 139.57	-37.87 ± 77.11	0.182	237.04 ± 171.11	149.85 ± 131.29	-87.19 ± 108.59	0.022
CRE	62.09 ± 37.21	57.07 ± 16.27	-5.02 ± 33.92	0.625	135.10 ± 69.11	115.06 ± 51.77	-20.04 ± 41.56	0.203
INR	1.63 ± 0.54	1.53 ± 0.54	-0.10 ± 0.45	0.534	1.79 ± 0.56	2.04 ± 0.51	0.25 ± 0.50	0.203

Variable	Child-pugh B(9)				Child-pugh C(n = 12)
	Baseline	Post-mean	Mean Diff	P value	Baseline	Post-mean	Mean Diff	P value
ALT	43.89 ± 42.09	71.68 ± 76.53	27.79 ± 84.57	0.139	122.50 ± 161.62	61.48 ± 52.36	-61.02 ± 164.58	0.583
AST	58.00 ± 43.38	93.47 ± 123.36	35.47 ± 124.68	0.11	156.33 ± 166.98	109.91 ± 102.82	-46.42 ± 209.08	0.638
TP	56.71 ± 5.91	55.51 ± 5.61	-1.20 ± 3.84	0.327	56.12 ± 10.87	64.75 ± 22.90	8.63 ± 25.46	0.158
ALB	29.79 ± 3.54	31.43 ± 3.44	1.64 ± 3.54	0.139	27.58 ± 5.02	30.78 ± 4.33	3.19 ± 4.88	0.084
TBIL	193.56 ± 139.80	140.90 ± 120.57	-52.65 ± 89.94	0.173	237.98 ± 171.56	170.09 ± 144.72	-67.88 ± 101.10	0.023
CRE	71.78 ± 31.27	78.67 ± 40.50	6.89 ± 17.68	0.374	115.67 ± 78.06	89.19 ± 52.82	-26.47 ± 42.64	0.117
INR	1.54 ± 0.39	1.47 ± 0.48	-0.07 ± 0.57	0.859	1.83 ± 0.62	1.99 ± 0.55	0.17 ± 0.43	0.272

ALT Alanine aminotransferase, AST Aspartate aminotransferase, TP Total protein, ALB Albumin, TBIL Total bilirubin, CRE Serum creatinine, INR International normalized ratio

In subgroup analyses, reductions in TBIL were observed in patients with more advanced liver dysfunction. Patients with MELD scores > 18 showed a decrease in TBIL (Δ = −87.19 ± 108.59 µmol/L, P = 0.022). A similar pattern was seen in patients with Child–Pugh class C (Δ = −67.88 ± 101.10 µmol/L, P = 0.023).

In patients with MELD ≤ 18 or Child–Pugh class B, TBIL levels showed no clear change from baseline (P > 0.05). Other liver and renal function parameters, including ALT, AST, TP, CRE, INR, and ALB, showed no consistent changes during the observation period (Table 4).

Discussion

In this study, we described posaconazole Cmin, target attainment, and adjustment patterns in patients with ESLD receiving prophylaxis. Most patients achieved Cmin within commonly used target ranges, although substantial inter-individual variability was observed. Dose adjustments were performed in a limited number of cases as part of routine clinical care. These findings support the use of TDM to better characterize drug exposure in patients with ESLD, a population in whom pharmacokinetic variability may be expected.

Posaconazole delayed-release tablets have been reported to provide relatively consistent systemic exposure and are less affected by gastrointestinal conditions, which may be relevant in patients with ESLD. In addition, their pharmacokinetic profile and limited involvement in cytochrome P450 metabolism suggest a relatively low potential for drug-drug interactions [6]. However, clinical data on this formulation in patients with ESLD remain limited.

In the present cohort, two patients (9.5%) developed breakthrough IFD. Both cases met criteria for probable IFD and receive diagnostic‑driven antifungal therapy. No IFD-related deaths were observed. These findings should be interpreted cautiously given the small sample size and the absence of a comparator group [3–5]. Routine GM testing was negative in all patients. Transient elevations in G were observed in several cases without sustained increases, which is consistent with the known limitations of this assay in patients with liver dysfunction [14]. Only one probable IFD patient showed persistently increasing G levels.

Posaconazole has been reported to show minimal overall pharmacokinetic differences between individuals with and without hepatic impairment [15]. However, data specifically addressing posaconazole exposure in patients with advanced hepatic impairment or ESLD remain limited. Therefore, previously reported concentrations in AML patients receiving posaconazole tablets were used as a contextual reference, with reported values of approximately 0.997 mg/L–1.310 mg/L [16], In present study, overall Cmin values were broadly comparable to these reported concentrations. However, this comparison should be interpreted cautiously and considered contextual rather than directly comparative, because the referenced AML study excluded patients with moderate or severe liver dysfunction, whereas the present cohort consisted of patients with ESLD. These findings should also be interpreted cautiously given the limited sample size.Substantial inter-individual variability in posaconazole exposure was observed in this cohort, which may be related to the complex clinical conditions seen in patients with ESLD, such as impaired hepatic function, gastrointestinal disturbances, and altered protein binding.

In this study, many patients had Cmin within the predefined reference range by day 3, while others reached comparable levels at later time points, generally within the first week. Compared with reports in individuals without hepatic impairment, in whom steady-state Cmin is often observed within one week [17], Cmin in this cohort appeared more variable over time, with relatively stable levels more commonly observed at later time points. A proportion of patients had Cmin values above 2.5 µg/mL during follow-up. Dose reductions were numerically more frequent among patients with Child–Pugh class C disease or MELD scores > 18; however, given the small sample size and limited number of dose-reduction events, this observation should be interpreted cautiously and does not allow firm conclusions regarding whether more severe hepatic impairment independently increases the likelihood of TDM-guided dose reduction. In patients who underwent dose adjustment, subsequent measurements were generally within the reference range [18]. These observations likely reflect routine clinical decision-making based on TDM rather than a predefined adjustment strategy. The reasons for delayed stabilization of Cmin in patients with ESLD are not fully understood. It is plausible that altered drug handling associated with advanced liver disease may contribute to this variability; however, such explanations remain speculative, as no formal pharmacokinetic modeling or comparative analysis was performed in this study [19]. Although no clear association between concomitant medications and Cmin was identified in the exploratory analysis restricted to pre-dose-adjustment measurements,, the small sample size limits the ability to detect potential effects of concomitant medications or other clinical factors on posaconazole exposure.

In ESLD, intestinal barrier dysfunction and disruption of the gut–liver axis [20] may alter drug handling, which could contribute to variability in systemic exposure. However, the underlying mechanisms remain incompletely understood and were not directly assessed in this study.

The upper threshold of 2.5 mg/L used in this study was informed by prior pharmacokinetic studies [8–9]. However, no universally accepted upper limit for posaconazole has been established, and the relationship between exposure and toxicity remains unclear. In this cohort, no concentration-related adverse events were identified. Therefore, dose adjustments at ≥ 2.5 mg/L should be viewed as a precautionary approach to limit high exposure, rather than reflecting a confirmed toxicity threshold.

Although therapeutic drug monitoring was frequently performed, formal exposure–response analyses were not feasible due to the small sample size, the limited number of breakthrough IFD events, and the absence of systematic recording of clinically relevant adverse events. Accordingly, any potential relationship between posaconazole exposure and clinical outcomes should be considered exploratory and hypothesis-generating.

Serial monitoring of hepatic and renal function showed no clear changes in patients with Child-Pugh class B disease or lower MELD scores. In patients with more advanced liver disease, reductions in TBIL were observed during follow-up. The reduction in TBIL is more likely to reflect concomitant supportive management-such as hepatoprotective therapy and albumin supplementation-rather than a direct effect of posaconazole. As these interventions were not systematically recorded, their impact could not be further evaluated.

Consistent with previous reports, higher posaconazole Cmin were not associated with clear evidence of hepatic deterioration, and overall tolerability appeared acceptable [21]. However, given impaired hepatic function in ESLD, higher systemic exposure may still raise theoretical safety concerns, supporting the use of therapeutic drug monitoring to better characterize exposure in this population. Given the small sample size (n = 21), the study was likely underpowered for subgroup analyses based on Child-Pugh class and MELD score. Therefore, the absence of statistically significant differences should not be interpreted as evidence of equivalence but may reflect limited statistical power.

The relationship between posaconazole exposure and adverse events could not be adequately assessed. Safety evaluation in this study was primarily based on laboratory parameters, while clinically relevant adverse events-such as gastrointestinal toxicity, QT prolongation, or other treatment-related complications-were not systematically recorded. As a result, these findings should be interpreted cautiously, and further studies with more comprehensive safety assessments are needed.

This study has several limitations. The inclusion of patients with different forms of advanced liver disease reflects the real-world nature of the cohort and may contribute to the observed variability. First, its single-center design and small sample size restrict the generalizability of the findings and limit the ability to detect uncommon adverse events. Second, the observational design precludes causal inference, particularly regarding potential clinical effects of prophylaxis. Third, limited follow-up and lack of post-discharge data prevented the evaluation of longer-term outcomes. Fourth, the small number of breakthrough infections limited further exploration analyses of potential risk factors. Finally, the requirement for at least two trough concentration measurements may have introduced selection bias, as patients with early discontinuation, rapid clinical deterioration, or intolerance may have been underrepresented.

Conclusion

In this cohort of patients with ESLD, most posaconazole Cmin measurements were within the predefined reference range of 0.5–2.5 mg/L, although both low and elevated concentrations were observed in a subset of measurements. Substantial inter-individual variability was noted, particularly during the early phase of treatment.These findings support the use of therapeutic drug monitoring and individualized dose adjustment to optimize posaconazole exposure in this clinically complex population. However, given the small sample size, limited number of clinical events, and the observational design, the results should be interpreted with caution and considered exploratory.

Abbreviations

ACLF

Acute-on-chronic liver failure

ALF

Acute liver failure

ALT

Alanine aminotransferase

AST

Aspartate aminotransferase

CLF

Chronic liver failure

Cmin

Trough concentration

EDTA

Ethylenediaminetetraacetic acid

ESLD

End-stage liver disease

EORTC/MSGERC

European organization for research and treatment of cancer/mycoses study group education and research consortium

G

(1,3)-β-D-glucan test

GM

Galactomannan test

HPLC–MS/MS

High-performance liquid chromatography–tandem mass spectrometry

IFD

Invasive fungal disease

INR

International normalized ratio

IQR

Interquartile range

MELD

Model for End-Stage Liver Disease

SALF

Subacute liver failure

TBIL

Total bilirubin

TDM

Therapeutic drug monitoring

TSQ

Triple quadrupole

Authors’ contributions

Tianyan Chen conceived and designed the study. Lei Shi, Xi Zhang, Xiaojing Liu, Yinghua Niu, Yingli He collected the data. Yunru Chen performed the data analysis. Yunru Chen drafted the manuscript. All authors critically revised the manuscript, read, and approved the final version.

Funding

Supported in part by a research grant from the Investigator-Initiated Studies Program of MSD. The opinions expressed in this paper are those of the authors and do not necessarily represent those of MSD.

Data availability

The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.

Declarations

Ethics approval and consent to participate

The study protocol was approved by the Ethics Committee of The First Affiliated Hospital of Xi’an Jiaotong University (Approval No. XJTU1AF2019LSK-071) and was conducted in accordance with the ethical standards of the institutional and/or national research committee and with the Declaration of Helsinki (as revised in 2013). Written informed consent was obtained from all participants prior to study inclusion. For participants under the age of 16 years, written informed consent to participate was obtained from their parents or legal guardians. All study procedures, including the intervention, data analysis, and blood sample collection, were performed after informed consent had been obtained.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.