Usefulness of the Albumin–Bilirubin Score in Determining the Initial Dose of Voriconazole for Patients with Liver Cirrhosis

Shunsuke Nashimoto; Shungo Imai; Mitsuru Sugawara; Yoh Takekuma

doi:10.1248/bpb.b22-00608

Abstract

The Child–Pugh score is widely used to assess liver function and estimate drug clearance in patients with liver cirrhosis. Recently, the albumin–bilirubin (ALBI) score, which objectively assesses liver function based only on albumin and total bilirubin levels, was developed as a new method. The purpose of this study was to analyze the relationship between the liver function assessment method and the plasma concentration of voriconazole (VRCZ), an antifungal drug for patients with liver cirrhosis. This single-center retrospective study enrolled 159 patients who received VRCZ between 2012 and 2020. In patients administered VRCZ orally, the median concentration to dose (C : D) ratio increased with the progression of Child–Pugh and ALBI grades. Positive correlations between the ALBI score and VRCZ C : D ratio were observed in patients with cirrhosis (r = 0.52 (95% confidence interval, 0.069–0.79); p < 0.05). In addition, a highly negative correlation was observed between the ALBI score and VRCZ daily maintenance dose (r=−0.79 (95% confidence interval, −0.92 to −0.50); p < 0.0001). In contrast, for patients administered VRCZ intravenously, no increase in C : D ratio was observed for both Child–Pugh and ALBI scores compared to the non-liver cirrhosis group. This may be because the injection is often used in severely ill patients, and factors other than impaired liver function may affect the plasma concentrations of VRCZ. In conclusion, the ALBI score was shown to be useful in predicting VRCZ clearance as well as the Child–Pugh score, and the initial dose of VRCZ might be determined according to the ALBI score.

INTRODUCTION

Estimating drug clearance based on the liver function of each patient is essential for achieving effective and safe drug therapy. In general, the Child–Pugh score, which includes serum bilirubin level, serum albumin level, prothrombin activity level, extent of ascites, and degree of hepatic encephalopathy, is used to assess liver function.¹⁾ However, this method is difficult to use in the accurate estimation of drug clearance in patients with liver cirrhosis because (1) some of the variables are subjective and require consultation with a specialist, for example, extent of ascites and degree of hepatic encephalopathy, and (2) it incorporates parameters that have an influence on each other, for example, serum albumin level and ascites. In contrast, the albumin–bilirubin (ALBI) score, which objectively assesses liver function based only on albumin and total bilirubin levels, was recently developed as a new method.²⁾ The ALBI score was developed as a treatment selection method for patients with hepatocellular carcinoma and has been reported to be more useful than the conventional Child–Pugh score in assessing hepatic reserve.^3–5) In addition, the ALBI score is highly accurate in classifying patients with mild liver dysfunction, compared to the Child–Pugh score.²⁾ Furthermore, the ALBI score can be easily calculated from biochemical laboratory data and is a continuous variable that may be applied to estimate drug clearance accurately compared with the Child–Pugh score.

Voriconazole (VRCZ) is a drug whose dosage is adjusted based on liver function. VRCZ is a broad-spectrum triazole antifungal agent used to treat refractory fungal infections and is metabolized by CYP2C19 and CYP3A4 in the liver.^6–8) Some studies have reported an association between VRCZ plasma concentrations and the successful clinical treatment of fungal infections.^9–11) However, excessive exposure to VRCZ increases the possibility of severe adverse effects.^12–15) Hence, therapeutic drug monitoring (TDM) is recommended for effective and safe treatment with VRCZ.^16,17) Several research groups have reported the necessity of dose reduction and frequent TDM in patients with severe liver cirrhosis (Child–Pugh class C).^18,19) Yamada et al. indicated that oral VRCZ maintenance dose in patients with Child–Pugh class C should be reduced to approximately one-third of that in patients with normal liver function.¹⁹⁾ In addition, it is recommended that the maintenance dose of VRCZ should be reduced to 50% of the usual dose in patients with mild to moderate liver cirrhosis (Child–Pugh class A or B).²⁰⁾ Although there are no reports on the relationship between the plasma concentration of VRCZ and ALBI score, VRCZ dosage for individual patients may be optimized by applying the ALBI score. The purpose of this study was to analyze the relationship between the plasma concentration of VRCZ and the liver function assessment method in patients with liver cirrhosis.

PATIENTS AND METHODS

Patients

This single-center retrospective study was conducted at Hokkaido University Hospital, Sapporo, Japan. Patients measured VRCZ plasma trough concentration between 2012 and 2020 were included in the study. Patients (1) under 18 years old; (2) received rifampicin, rifabutin, carbamazepine, phenytoin, letermovir, and anti-human immunodeficiency virus drugs concomitantly; (3) measured plasma concentration with loading dose by day 2 or less after initiation of VRCZ; (4) measured plasma concentration without loading dose by day 3 or less after initiation of VRCZ; (5) with dose adjustment before measurement, except for the loading dose; (6) with missing laboratory data required for calculation of the Child–Pugh and ALBI scores; and (7) admitted to the intensive care unit were excluded from this study. The steady state concentration in this study was defined as the number of days between blood sample collection and initiation of VRCZ with a loading dose of ≧ 3, and as that without a loading dose of ≧ 4 in a previous study.²¹⁾

Patient medical records were individually reviewed to collect clinical information, such as age, sex, diagnosis, clinical department, body weight, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, γ-glutamyl transpeptidase, albumin, total bilirubin, prothrombin time, serum creatinine, C-reactive protein, presence or absence of cirrhosis, VRCZ dosage, and concomitant drugs during VRCZ treatment.

Measurement of VRCZ Plasma Concentration

TDM was performed at Hokkaido University Hospital. VRCZ trough samples were collected within 30 min before the next administration, and the VRCZ dosage was adjusted based on these results.

Only the first TDM results were used in the analysis for each patient. All patients were administered VRCZ twice a day. Plasma VRCZ concentrations were determined using a previously validated HPLC-UV method up to 2019 and LC/MS/MS method from 2019.¹⁹⁾

Relationship between Liver Function Assessment Method and VRCZ Plasma Concentration

We compared the trough plasma concentration at steady state, daily maintenance dose (mg/kg/d), and concentration-to-dose (C : D) ratio of VRCZ of Child–Pugh class A/B/C and ALBI grade 1/2/3. The Child–Pugh class was defined as follows: grade A, 5–6 points; grade B, 7–9 points; and grade C, 10–15 points.¹⁾ The extent of ascites and degree of hepatic encephalopathy were evaluated based on patient diagnosis and medical records. The ALBI score was calculated using the formula 0.66× log₁₀(total bilirubin (mg/dL) × 17.1) − (0.085× albumin (g/dL) × 10). The ALBI score was categorized as grade 1 (−2.60 or less), grade 2 (−2.59 to −1.39), or grade 3 (more than −1.39).²⁾ The correlation between the ALBI score, VRCZ C : D ratio, and daily maintenance dose was analyzed only in patients with cirrhosis.

Statistical Analysis

Data are presented as median and interquartile range. Differences between groups were compared using the Kruskal–Wallis test followed by the Steel–Dwass test as a post hoc test. Univariate analysis was used to analyze the correlation between the ALBI score, VRCZ C : D ratio, and daily maintenance dose. All statistical analyses were performed using JMP^® Pro 16 software (SAS Institute Inc., Cary, NC, U.S.A.). Statistical significance was set at p < 0.05.

Ethics

This study was conducted in accordance with the Declaration of Helsinki and its amendments. The study protocol was approved by the Ethics Committee of Hokkaido University Hospital (Protocol No. 020-0421).

RESULTS

Clinical Background of Enrolled Patients

One hundred and fifty-nine patients received VRCZ between 2012 and 2020 were enrolled in this study. One hundred and seven patients received voriconazole orally, and 52 patients received voriconazole intravenously. For patients who received VRCZ both orally and intravenously, only the first-reported TDM results were included in the analysis. The backgrounds of the patients who received VRCZ orally are shown in Table 1, and those of the patients who received VRCZ intravenously are shown in Table 2. In Table 1, 61.7% of the patients were male, with a median age of 58 (interquartile range 48–68) years, while in Table 2, 59.6% of the patients were male, with a median age of 62 (52–74) years. In both Tables 1 and 2, the median serum albumin levels were lower than the reference values (4.1–5.1 g/dL). VRCZ plasma concentration tended to be higher after injection than after oral administration and exceeded the recommended range (1–4 µg/mL) in 35.8% of the patients.

Table 1. Characteristics for Patients Administered VRCZ Orally (n = 107)

Parameters	Value
Age (years)^a⁾	58 (48–68)
Male/Female^b⁾	66/41
Body weight (kg)^a⁾	58.0 (45.2–64.6)

AST (IU/L)^a⁾	29 (19–41)
ALT (IU/L)^a⁾	28 (15–56)
ALP (IU/L)^a⁾	339 (236–514)
γ-GTP (IU/L)^a⁾	68 (36–149)
Albumin (g/dL)^a⁾	3.0 (2.6–3.5)
Total bilirubin (mg/dL)^a⁾	0.7 (0.5–1.0)
PT (%)^a⁾	91.7 (76.7–101.1)
Serum creatinine (mg/dL)^a⁾	0.77 (0.59–1.13)
CRP (mg/dL)^a⁾	1.44 (0.24–4.88)

VRCZ concentration (µg/mL)^a⁾	2.32 (1.16–3.86)
VRCZ concentration measurement date after loading dose^a⁾	7 (5–9)
With loading dose/Without loading dose/Unknown^c⁾	92/12/3
VRCZ loading dose for Non-LC patients (mg/kg/d)^a^),^d⁾	10.03 (8.83–11.97)
VRCZ loading dose for Child–Pugh class A and B patients (mg/kg/d)^a^),^d⁾	9.42 (8.30–13.15)
VRCZ loading dose for Child–Pugh class C patients (mg/kg/d)^a^),^d⁾	7.16 (3.75–10.24)
VRCZ maintenance dose for Non-LC patients (mg/kg/d)^a⁾	6.36 (5.21–7.34)
VRCZ maintenance dose for Child–Pugh class A and B patients (mg/kg/d)^a⁾	4.80 (4.01–5.67)
VRCZ maintenance dose for Child–Pugh class C patients (mg/kg/d)^a⁾	2.39 (1.73–3.14)

Diagnosis and treatment department
Hematology/Gastrointestinal surgery/Rheumatology/Other^e⁾	67/12/8/20

a) Data are expressed as the median (interquartile range), b) Data are expressed as n/n, c) Data are expressed as n/n/n. Three patients were started VRCZ treatment at another center, so it was unknown whether loading dose was administered, d) Only for patients receiving the loading dose, e) Data are expressed as n/n/n/n. AST; aspartate aminotransferase, ALT; alanine aminotransferase, ALP; alkaline phosphatase, γ-GTP; γ-glutamyl transpeptidase, PT; prothrombin time, CRP; C-reactive protein, VRCZ; voriconazole, LC; liver cirrhosis.

Table 2. Characteristics of Patients Administered VRCZ Intravenously (n = 52)

Parameters	Value
Age (years)^a⁾	62 (52–74)
Male/Female^b⁾	31/21
Body weight (kg)^a⁾	53.6 (46.0–62.0)

AST (IU/L)^a⁾	24 (16–40)
ALT (IU/L)^a⁾	27 (12–44)
ALP (IU/L)^a⁾	295 (236–469)
γ-GTP (IU/L)^a⁾	57 (38–158)
Albumin (g/dL)^a⁾	2.6 (2.3–3.1)
Total bilirubin (mg/dL)^a⁾	0.5 (0.3–0.9)
PT (%)^a⁾	86.7 (73.2–92.6)
Serum creatinine (mg/dL)^a⁾	0.68 (0.53–0.81)
CRP (mg/dL)^a⁾	3.92 (1.63–9.21)

VRCZ concentration (µg/mL)^a⁾	3.32 (1.90–4.59)
VRCZ concentration measurement date after loading dose^a⁾	7 (5–7)
With loading dose/Without loading dose/Unknown^c⁾	50/2/0
VRCZ loading dose for Non-LC patients (mg/kg/d)^a^),^d⁾	11.90 (11.30–12.24)
VRCZ loading dose for Child–Pugh class A and B patients (mg/kg/d)^a^),^d⁾	11.04 (9.81–12.09)
VRCZ maintenance dose for Non-LC patients (mg/kg/d)^a⁾	7.42 (6.25–8.02)
VRCZ maintenance dose for Child–Pugh class A and B patients (mg/kg/d)^a⁾	5.66 (4.09–7.93)

Diagnosis and treatment department
Hematology/Gastrointestinal surgery/Pulmonology/Other^e⁾	17/8/5/22

a) Data are expressed as the median (interquartile range), b) Data are expressed as n/n, c) Data are expressed as n/n/n, d) Only for patients receiving the loading dose, e) Data are expressed as n/n/n/n. AST; aspartate aminotransferase, ALT; alanine aminotransferase, ALP; alkaline phosphatase, γ-GTP; γ-glutamyl transpeptidase, PT; prothrombin time, CRP; C-reactive protein, VRCZ; voriconazole, LC; liver cirrhosis.

VRCZ C : D Ratio for Each Liver Function Assessment Method

For patients administered VRCZ orally, the median C : D ratio increased with the progression of Child–Pugh class and ALBI grade (Figs. 1(a), (b)). The C : D ratio significantly increased in patients who were Child–Pugh class C compared with the non-liver cirrhosis (Non-LC) group (Hodges–Lehmann median difference 0.81 (95% confidence interval, 0.41–1.12); p = 0.0013). Furthermore, the C : D ratio significantly increased in patients with ALBI grade 3 compared with the non-LC group (Hodges–Lehmann median difference 0.53 (95% confidence interval, 0.18–0.97); p = 0.0032). The maintenance dose was decreased significantly only in the ALBI 3 group in patients receiving VRCZ orally compared with the non-LC group (Hodges–Lehmann median difference −3.23 [95% confidence interval, −4.58 to −1.90]; p < 0.0001) and ALBI 2 group (Hodges–Lehmann median difference −2.23 (95% confidence interval, −4.09 to −0.0083]; p = 0.028, Supplementary Fig. S1). In contrast, for patients administered VRCZ intravenously, the C : D ratio did not increase in patients with cirrhosis compared with the non-LC group (Figs. 1(c), (d)). The median VRCZ plasma concentrations in all groups were within the recommended range for patients who received VRCZ orally (Figs. 2(a), (b)). In contrast, for patients who received VRCZ intravenously, the median VRCZ plasma concentrations in the ALBI grade 3 group exceeded 4 µg/mL (Figs. 2(c), (d)), although no statistically significant differences were observed.

Fig. 1. VRCZ C : D Ratio for Each Liver Function Assessment Method

The distribution of the C : D ratio for each Child–Pugh class (a) or ALBI grade (b) was obtained in patients who received VRCZ orally. The distribution of the C : D ratio for each Child–Pugh class (c) or ALBI grade (d) was also obtained in patients who received VRCZ intravenously. The C : D ratio was calculated as the dose-normalized VRCZ concentration measured at steady state. ** indicates significant difference based on the Kruskal–Wallis test followed by the Steel–Dwass test as a post hoc test (p < 0.01). C : D; concentration to dose, ALBI; albumin-bilirubin, VRCZ; voriconazole, LC; liver cirrhosis.

Fig. 2. VRCZ Concentration for Each Liver Function Assessment Method

The distribution of the concentration of Child–Pugh class (a) or ALBI grade (b) was obtained in patients who received VRCZ orally. The distribution of the concentration of Child–Pugh class (c) or ALBI grade (d) was also obtained in patients who received VRCZ intravenously. ALBI; albumin–bilirubin, VRCZ; voriconazole.

The Correlation between ALBI Score, C : D Ratio, and VRCZ Daily Maintenance Dose

Next, the correlation between the ALBI score, VRCZ C : D ratio, and daily maintenance dose was analyzed only in patients with cirrhosis. The number of enrolled patients diagnosed with liver cirrhosis in the electronic medical records was 23. The grade distribution of each liver function assessment method in patients with cirrhosis is shown in Table 3. Only one patient was classified as ALBI grade 1. Patients with ALBI grade 2 were classified as A or B according to the Child–Pugh classification, and patients with ALBI grade 3 were classified as B or C, respectively.

Table 3. The Grade Distribution of Each Liver Function Assessment Method in Patients with Cirrhosis ((a) Patients Received VRCZ Orally (b) Patients Received VRCZ Intravenously)

(a)
ALBI grade Child–Pugh class	1	2	3
A	1	3	0
B	0	4	3
C	0	0	7
(b)
ALBI grade Child–Pugh class	1	2	3
A	0	1	0
B	0	0	4
C	0	0	0

ALBI; albumin–bilirubin.

Figure 3 shows positive correlations between ALBI score and VRCZ C : D ratio in patients received VRCZ orally (r = 0.52 (95% confidence interval, 0.069–0.79); p < 0.05). In addition, the highly negative correlation was also observed between ALBI score and VRCZ daily maintenance dose (r = −0.79 (95% confidence interval, −0.92–−0.50); p < 0.0001).

Fig. 3. The Correlation between ALBI Score, C : D Ratio, and Daily Maintenance Dose in Patients with Cirrhosis Received VRCZ Orally

Each value represents the C : D ratio of VRCZ (a) or daily maintenance dose (b). The linear regression curve is presented with a 95% confidence interval. ALBI; albumin–bilirubin, C : D; concentration to dose, VRCZ; voriconazole.

DISCUSSION

In patients with liver dysfunction, the plasma concentration of VRCZ increases due to a decrease in hepatic clearance. The saturated metabolism of VRCZ in the liver contributes to its nonlinear pharmacokinetic profile.²²⁾ Therefore, TDM is recommended to ensure its safety and efficacy in patients with liver dysfunction.^23,24) In this study, the relationship between VRCZ plasma concentration and liver function assessment method was analyzed in patients with liver cirrhosis.

One hundred and fifty-nine patients who received VRCZ between 2012 and 2020 were enrolled in this study. In this population, serum albumin levels were lower than reference values (4.1–5.1 g/dL). This may be due to (1) the inclusion of cirrhotic patients in the analysis and (2) supine blood collection, which decreases the apparent serum albumin concentration. Plasma VRCZ concentrations were determined using the HPLC-UV method up to 2019 and LC/MS/MS method from 2019 onwards.¹⁹⁾ Both are validated measurement methods and it is thought that there is no difference in concentration between the methods.

For patients administered VRCZ orally, the median VRCZ C : D ratio increased with the progression of Child–Pugh class and ALBI grade (Figs. 1(a), (b)). In this study, the C : D ratio of the non-LC group was 0.322 (interquartile range 0.210–0.622) and that of the Child–Pugh class C group was 1.25 (interquartile range 0.871–1.408), which is consistent with the results of previous studies.¹⁹⁾ The C : D ratio of the ALBI 3 group was also 1.03 (interquartile range 0.544–1.307), which was significantly different from that of the non-LC group. These results suggest that the ALBI score, as well as the Child–Pugh score, is useful in determining VRCZ dosage for patients with liver dysfunction. The ALBI score can be conveniently calculated from laboratory data; therefore, it might be superior to the Child–Pugh score. Although previous reports have indicated that the ALBI score might more accurately assess liver function in patients with mild liver dysfunction,²⁾ there was no significant increase in the C : D ratio and maintenance dose between patients with mild liver cirrhosis and non-LC patients in this study (Fig. 1(b), Supplementary Fig. S1). These results suggest that VRCZ clearance is preserved in patients with mild liver dysfunction and that dose reduction may not be necessary in these patients.

In contrast, no relationship between the ALBI score and C : D ratio was observed in patients received VRCZ intravenously, although the sample size was small (Figs. 1(c), (d)). This may be because the injection is often used in severely ill patients, and factors other than impaired liver function may affect the plasma concentration of VRCZ. We considered that one of the factors affecting VRCZ pharmacokinetics was the degree of inflammation. Fungal infections activate the immune system, resulting in increased levels of proinflammatory cytokines, such as interleukin-6 by increased CRP levels.^25,26) Increased interleukin-6 levels reduce the mRNA expression of CYP2C19 by 30–50% in human hepatocytes.²⁶⁾ Previous clinical studies have reported a positive correlation between CRP and VRCZ concentrations.^27,28) The CRP level was higher in patients who received VRCZ intravenously than in those who received VRCZ orally (Tables 1 and 2), and it is possible that this may have affected the VRCZ C : D ratio.

It is possible to analyze the correlation of the ALBI score with the VRCZ C : D ratio and the daily maintenance dose because it is a continuous variable. Figure 3 shows the correlation between ALBI score, C : D ratio, and daily maintenance dose in patients with cirrhosis received VRCZ orally. The ALBI scores significantly correlated with the C : D ratio and the daily maintenance dose of VRCZ. The VRCZ package insert recommends reducing the maintenance dose by 50% in patients with Child–Pugh class A or B.¹⁹⁾ This result suggests that the maintenance dose of VRCZ, which was previously determined subjectively, may be reduced only according to ALBI score.

Our study has some limitations. First, the genetic polymorphism of CYP2C19, a major VRCZ-metabolizing enzyme in the liver, has not been determined. Kubota et al. reported that approximately 20% of the Japanese population are CYP2C19 poor metabolizers.²⁹⁾ The C : D ratio may be further increased in poor metabolizers. One patient underwent TDM on day 3, and 9 patients who underwent TDM day 4 were included in this study. If these patients were poor metabolizers, a steady state calculation was not possible. Another previous study also indicated that VRCZ pharmacokinetics are strongly affected by the CYP2C19 genotype, and determining the genotype before VRCZ initiation may facilitate the ability to achieve therapeutic plasma levels without reaching out-of-range levels.^30–32) Second, this was a single-center, retrospective study, and only 23 patients were diagnosed with liver cirrhosis. Future multicenter studies should be designed to confirm the correlation between the ALBI score and VRCZ clearance through multivariate analysis.

In conclusion, the ALBI score was shown to be potentially useful in estimating VRCZ clearance, and the initial dose of VRCZ might be determined according to the ALBI score value.

Conflict of Interest

The authors declare no conflict of interest.

Supplementary Materials

This article contains supplementary materials.

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