International Journal of Infectious Diseases 93 (2020) 345–352

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International Journal of Infectious Diseases

journal homepage: www.elsevier.com/locate/ijid

Pharmacokinetics of intravenous voriconazole in patients with

liver dysfunction: A prospective study in the intensive care unit$
Xiao-bin Lina,1, Fa Huangb,1, Li Tongb , Yan-zhe Xiaa , Jing-jing Wua , Jia Lia ,
Xiao-guang Hub , Tao Liangc, Xiao-man Liua , Guo-ping Zhongd, Chang-jie Caib,** ,
Xiao Chena,*
a
Department of Pharmacy, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, China
b
Department of Critical Care Medicine, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, China
c
School of Pharmacy, Xinhua College of Sun Yat-sen University, Guangzhou 510520, China
d
Institute of Clinical Pharmacology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510080, China

A R T I C L E I N F O A B S T R A C T

Article history: Objectives: To characterize the pharmacokinetics (PK) of intravenous voriconazole (VRC) in critically ill
Received 29 November 2019 patients with liver dysfunction.
Received in revised form 18 February 2020 Methods: Patients with liver dysfunction in the intensive care unit (ICU) were included prospectively. The
Accepted 19 February 2020
Child–Pugh score was used to categorize the degree of liver dysfunction. The initial intravenous VRC
dosing regimen comprised a loading dose of 300 mg every 12 h for the first 24 h, followed by 200 mg
Keywords: every 12 h. The first PK curves (PK curve 1) were drawn within one dosing interval of the first dose for 17
Voriconazole
patients; the second PK curves (PK curve 2) were drawn within one dosing interval after a minimum of
Liver dysfunction
Pharmacokinetics
seven doses for 12 patients. PK parameters were estimated by non-compartmental analysis.
Child–Pugh score Results: There were good correlations between the area under the curve (AUC0–12) of PK curve 2 and the
corresponding trough concentration (C0) and peak concentration (Cmax) (r2 = 0.951 and 0.963,
respectively; both p < 0.001). The median half-life (t1/2) and clearance (CL) of patients in Child–Pugh class
A (n = 3), B (n = 5), and C (n = 4) of PK curve 2 were 24.4 h and 3.31 l/h, 29.1 h and 2.54 l/h, and 60.7 h and
2.04 l/h, respectively. In the different Child–Pugh classes, the CL (median) of PK curve 2 were all lower
than those of PK curve 1. The apparent steady-state volume of distribution (Vss) of PK curve 1 was
positively correlated with actual body weight (r2 = 0.450, p = 0.004). The median first C0 of 17 patients
determined on day 5 was 5.27 (2.61) mg/ml, and 29.4% of C0 exceeded the upper limit of the therapeutic
window (2–6 mg/ml).
Conclusions: The CL of VRC decreased with increasing severity of liver dysfunction according to the Child–
Pugh classification, along with an increased t1/2, which resulted in high plasma exposure of VRC. Adjusted
dosing regimens of intravenous VRC should be established based on Child–Pugh classes for these ICU
patients, and plasma concentrations should be monitored closely to avoid serious adverse events.
© 2020 The Authors. Published by Elsevier Ltd on behalf of International Society for Infectious Diseases.
This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-
nd/4.0/).

$
This clinical study is registered in the Chinese Clinical Trial Registry (http://
Introduction
www.chictr.org.cn, registration number ChiCTR1800019472).
* Corresponding author at: Department of Pharmacy, The First Affiliated Hospital
of Sun Yat-sen University, No. 58, Zhongshan 2nd Road, Guangzhou 510080, China. Patients with liver dysfunction, especially those in the intensive
** Corresponding author at: Department of Critical Care Medicine, The First care unit (ICU), become susceptible to fungi because of decreased
Affiliated Hospital of Sun Yat-sen University, No. 58, Zhongshan 2nd Road,
immune function and increased intestinal permeability (Koulenti
Guangzhou 510080, China.
E-mail addresses: linxb6@mail2.sysu.edu.cn (X.-b. Lin), et al., 2014; Yamada et al., 2018). The mortality of invasive
huangf56@mail2.sysu.edu.cn (F. Huang), tongli2@mail.sysu.edu.cn (L. Tong), aspergillosis in these patients is extremely high (Chen et al., 2013;
sumtreexyz@163.com (Y.-z. Xia), wujingjingsysu@163.com (J.-j. Wu), Jeurissen et al., 2013). Voriconazole (VRC), a second-generation
pharma_jiali@163.com (J. Li), huxiaog@mail.sysu.edu.cn (X.-g. Hu), triazole with potent broad-spectrum antifungal activity, is
ltao_work@163.com (T. Liang), 56873620@qq.com (X.-m. Liu),
zhonggp@mail.sysu.edu.cn (G.-p. Zhong), caichjie@mail.sysu.edu.cn (C.-j. Cai),
recommended as a first-line agent for the treatment of invasive
chenx5@mail.sysu.edu.cn (X. Chen). aspergillosis (Patterson et al., 2016) and as an alternative therapy
1
Xiao-bin Lin and Fa Huang contributed equally to this work. for candidemia (Pappas et al., 2016).

https://doi.org/10.1016/j.ijid.2020.02.041
1201-9712/© 2020 The Authors. Published by Elsevier Ltd on behalf of International Society for Infectious Diseases. This is an open access article under the CC BY-NC-ND
license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
346 X.- Lin et al. / International Journal of Infectious Diseases 93 (2020) 345–352
VRC is metabolized in the liver principally by the cytochrome
P450 (CYP) 2C19 isoenzyme and, to a lesser extent, by CYP3A4 and
CYP2C9 (Hyland et al., 2003). A growing number of studies have
shown that CYP2C19 polymorphisms make a crucial contribution
to the extensive pharmacokinetic (PK) variability of VRC (Lee et al.,
2012; Li et al., 2017; Lin et al., 2018; Wang et al., 2014a).
Additionally, age, liver function, co-medications, and inflammation
could also contribute to PK variability (Dolton et al., 2014;
Theuretzbacher et al., 2006; Veringa et al., 2017; Wang et al.,
2014a). The efficacy and toxicity of VRC are considered to be
significantly correlated with plasma trough concentrations (C0),
and the narrow therapeutic range has been identified. Therefore,
therapeutic drug monitoring (TDM) of VRC is widely recom-
mended in clinical practice to maximize efficacy and minimize
toxicity (Dolton and McLachlan, 2014).
The liver plays an important role in the hepatic metabolism or
biliary excretion of the majority of medicines, and it may affect
plasma protein binding, thus affecting the distribution and
elimination of drugs (Verbeeck, 2008). One study (Alffenaar
et al., 2009) reported that decreased hepatic function could
significantly reduce VRC metabolism, resulting in high plasma VRC
levels. Recently, supratherapeutic C0 of VRC under empirical
treatment regimens were observed in patients with moderate and
serious hepatic cirrhosis (Child–Pugh class B and C) in studies by
Wang et al. (Wang et al., 2018a, 2018b). Elevated VRC concen-
trations may increase the risk of adverse reactions such as
neurotoxicity, visual disturbances, and potential hepatotoxicity
(Dolton and McLachlan, 2014).
The non-linear PK, significant inter-individual variability, and
narrow therapeutic range of VRC (Dolton et al., 2014) may
complicate its optimal use in ICU patients and further affect the
prognosis of critically ill patients with liver dysfunction. Therefore,
it is vital to refine VRC therapy to improve clinical outcomes for
these patients. However, it appears that data on the PK and dosage
optimization of intravenous VRC in critically ill patients with liver
dysfunction are limited. The main aim of this prospective study
was to characterize the PK of intravenous VRC in ICU patients with
liver dysfunction by non-compartmental analysis.
Patients and methods
Study population
A prospective observational clinical study was conducted from
November 2018 to August 2019 in the Department of Critical Care
Medicine, the First Affiliated Hospital of Sun Yat-sen University.
The study was approved by the Ethics Committee of the First
Affiliated Hospital of Sun Yat-sen University (approval number
201848). All patients with liver dysfunction aged 18 years or older
receiving intravenous VRC were eligible to be enrolled in the study,
and signed informed consent was obtained from participants
themselves or their legal guardians before enrollment. The Child–
Pugh classification system was used to categorize the liver function
of the patients into mild (Child–Pugh score of 5–6), moderate
(Child–Pugh score of 7–9), or severe (Child–Pugh score >9) degree
of hepatic impairment. The exclusion criteria were as follows: (1)
concomitant use of strong CYP450 enzyme inhibitors or inducers
(e.g., rifampicin and phenytoin); (2) application of extracorporeal
membrane oxygenation; (3) absence of plasma VRC levels; (4)
absence of important dosing information or clinical data (missing
data).
Study design
The initial intravenous (approximately 1-h infusion) VRC
(VFEND, Pfizer) dosing regimen comprised a loading dose of 300
mg every 12 h for the first 24 h, followed by a maintenance dose
of 200 mg every 12 h. A PK curve (PK curve 1) was drawn at t = 0
(pre-dose), 1, 2, 4, 6, 8, and 12 h from the start of the first VRC
infusion; a second PK curve (PK curve 2) was drawn at similar
sampling time-points after the administration of at least seven
doses. Additional C0 samples were collected within 30 minutes
before the next dose based on routine clinical TDM.
Data collection
A standardized data collection form was used to individually
review the medical records of the patients. Researchers closely
recorded the dosing information (e.g., VRC dose, administration
time, duration of infusion, and sampling time), co-medications
such as proton pump inhibitors (PPIs), and biochemical indices
starting at patient enrolment. In addition, demographic data (age,
sex, and actual body weight) and disease scores (Acute Physiology
and Chronic Health Evaluation (APACHE) II score within 24 h of ICU
admission, sequential organ failure assessment (SOFA) score at
baseline, and Child–Pugh score) were collected.
Analytical assays
All VRC plasma concentrations were determined using a
validated high-performance liquid chromatography–tandem mass
spectrometry method (HPLC-MS/MS). D3-voriconazole was used
as the internal standard. Chromatographic separation was
performed on a Hypersil GOLD C18 column (50 mm  4.6 mm,
5 mm; Thermo Scientific) with an isocratic mobile phase consisting
of A (aqueous phase: 0.1% formic acid) and B (organic phase:
acetonitrile) (A:B = 60:40, v/v), column temperature of 30  C, flow
rate of 0.4 ml/min, and a total run time of 5.5 min. The multiple
reaction monitoring (MRM) transitions with an electrospray
ionization source in the positive mode, m/z 350.0 → 281.0 for
VRC and 353.1 → 284.1 for D3-voriconazole, were conducted on a
triple-quadrupole tandem mass spectrometer to detect VRC. The
plasma sample was pretreated by precipitating with acetonitrile.
The linearity range was 0.10 to 30.00 mg/ml. The intra-day and
inter-day precisions were within 1.23–1.95% and 1.73–2.57%,
respectively. The mean extraction recovery ranged from 101.08%
to 104.92%. A matrix effect on VRC was not observed with this
method. Stability tests showed that VRC was stable in plasma at
room temperature for 24 h and at 20  C in three repeated freeze–
thaw cycles, with tested recoveries between 96.30% and 102.06%.
DNA purification and CYP2C19 genotyping
A blood sample (1 ml) was drawn from each enrolled non-
liver transplant patient for genotype detection. DNA was
purified with the Nucleic Acid Extraction Reagent (Shanghai
BaiO Technology Co., Ltd, Shanghai, China). The genotyping of
deficient alleles CYP2C19*2 and *3 was performed using the DNA
microarray chip method with CYP2C19 Gene Detection Kit
(Shanghai BaiO Technology Co., Ltd, Shanghai, China). CYP2C19
genotypes were classified into six categories: *1/*1, *1/*2, *1/*3,
*2/*2, *2/*3, and *3/*3.
Pharmacokinetic analysis
A non-compartmental analysis was performed using Phoenix
WinNonlin software (version 7.0; Certara LP, Pharsight, St. Louis,
MO, USA) to calculate the PK parameters of PK curve 1 and PK curve
2. The major parameters included the terminal half-life (t1/2), peak
concentration (Cmax), time to reach Cmax (Tmax), apparent steady-
state volume of distribution (Vss), clearance (CL), and the area
under the concentration–time curve from 0 h to 12 h (AUC0–12).
 X.- Lin et al. / International Journal of Infectious Diseases 93 (2020) 345–352
Statistical analysis
Continuous variables were presented as the median and
interquartile range (IQR) and categorical variables were reported
as frequencies and percentages. The correlations between AUC0–12
of PK curve 2 and the corresponding C0 and Cmax were evaluated
using a simple linear regression model. One-way analysis of
variance (ANOVA) with Bonferroni post hoc test was used to
compare the difference in first C0 among the Child–Pugh classes.
Simple linear regression analysis was used to evaluate the
correlations between PK parameters and the clinical character-
istics and biochemical indices of the patients. A two-sided p-value
of <0.05 was considered statistically significant. The statistical
analysis was performed using IBM SPSS software version 24.0 (IBM
Corp., Armonk, NY, USA).
Results
Patient characteristics
A total of 17 patients were included in the study. PK curve 1 was
drawn within one dosing interval of the first dose for all 17
patients; PK curve 2 was drawn within one dosing interval after a
minimum of seven doses (range 7 to 15 doses; median 12 doses) for
12 patients (PK profiles are shown in Figure 1; and the actual
sampling times and number of samples per subject are presented
in Supplementary MaterialTable S1). The demographic and
clinical characteristics of the 17 patients (PK curve 1) and the 12
patients (PK curve 2) are summarized in Table 1. The range of actual
body weight of the 17 patients was 48–87 kg (median 58 kg). The
subjects were divided into three categories based on the degree of
liver dysfunction: four were Child–Pugh class A, eight were class B,
and five were class C. Four categories of CYP2C19 genotypes were
observed in the 12 non-liver transplant patients: *1/*1 (n = 5), *1/*2
(n = 5), *2/*2 (n = 1), and *2/*3 (n = 1). The frequencies of deficient
alleles CYP2C19*2 and*3 were 33.3% and 4.2%, respectively.
Pharmacokinetics results
The PK parameters of intravenous VRC in the 17 patients (PK curve
1) and the 12 patients (PK curve 2), as well as in the different Child–
Pugh classes, are presented in Tables 2 and 3. The Tmax, Cmax, Vss, and
AUC0–12 of PK curve 1 did not include patient 14, because Cmax was
not obtained for this patient. As shown in Figure 2, there were good
correlations between AUC0–12 of PK curve 2 and the corresponding
C0 and Cmax (r2 = 0.951 and 0.963, respectively; both p < 0.001).
Figure 1. Plasma concentration vs. time curves of intravenous voriconazole in patients with liver dysfunction. (A) Individual plasma concentration vs. time curves (PK curve 1)
for 17 patients during an intravenous infusion (300 mg, approximately 1-h infusion) dosing interval of the first dose. (B) Individual plasma concentration vs. time curves (PK
curve 2) for 12 patients during an intravenous infusion (200 mg, approximately 1-h infusion) dosing interval of a minimum of seven doses (range 7 to 15 doses; median 12
doses). Abbreviation: PK, pharmacokinetics.
347
PK curve 2 was drawn at a median of the 15th dose,12th dose, and
11th dose for Child–Pugh class A (n = 3), B (n = 5), and C (n = 4)
patients, respectively. As the degree of hepatic impairment
increased, the CL of VRC of PK curve 1 and PK curve 2 decreased
(Child–Pugh class A > B > C) and the t1/2 and the AUC0–12 of PK curve
2 increased (Child–Pugh class A < B < C) (Table 3 and Figure 3).
However, the differences in these PK parameters were not
statistically significant among the three Child–Pugh classes, except
for CL in PK curve 1 (p = 0.012). Additionally, the CL (median) in PK
curve 2 was lower than that in PK curve 1 for patients of all three
Child–Pugh classes (Table 3 and Figure 3).
The median (IQR) first C0 of the 17 patients was 5.27 (2.61) mg/
ml. The median sampling time for the first C0 was day 5 (range day
4–7). Only two C0 values were less than the lower limit of the
therapeutic window (2–6 mg/ml), whereas 29.4% (5/17) of the first
C0 exceeded the upper limit of 6 mg/ml. Furthermore, the first C0
was elevated with increased degree of hepatic impairment (Child–
Pugh class A < B < C), but only the difference in C0 between Child–
Pugh class C and A patients was significant (p = 0.030; Figure 4).
The median (IQR) of the first C0 in Child–Pugh class A (n = 4), B
(n = 8), and C (n = 5) patients was 2.41 (3.57), 5.22 (2.06), and 5.96
(4.18) mg/ml, respectively; the median sampling time for the first
C0 was day 5, day 5, and day 4, respectively.
The significant correlations between the PK parameters and the
clinical characteristics and biochemical indices of the patients,
determined by simple linear regression, are summarized in Table 4
and Figure 5. The t1/2 of PK curve 2 extended with elevated
international normalized ratio (INR) (r2 = 0.510); AUC0–12 of PK
curve 2 increased with elevated aspartate aminotransferase (AST)
(r2 = 0.612) and total bilirubin (TBIL) (r2 = 0.515). Vss of PK curve 1
was positively correlated with actual body weight (r2 = 0.450), and
the correlation was significantly improved (r2 = 0.707) when an
outlier of Vss (309.21 l) from patient 3 was omitted (Figure 5). In
addition, there was a negative correlation between AUC0–12 of PK
curve 1 and body weight (r2 = 0.614). The study did not observe
significant associations between the PK parameters and other
clinical characteristics (e.g., APACHE II score, SOFA score at
baseline, CYP2C19 genotype, and concomitant use of PPIs
(esomeprazole vs. pantoprazole) and VRC).
Discussion
To date, the PK profile of intravenous VRC in critically ill patients
with liver dysfunction has not been studied. The current
prospective study of 17 ICU patients with hepatic impairment
receiving a standard VRC dosing regimen, investigated the PK
348 X.- Lin et al. / International Journal of Infectious Diseases 93 (2020) 345–352

Table 1
Demographic and clinical data; median (IQR, range).

Characteristic PK curve 1 (n = 17) PK curve 2 (n = 12)

First C0 (mg/ml) 5.27 (2.61, 1.72–10.07) 5.42 (4.37, 1.87–10.07)
Sampling time for first C0 (days) 5 (1, 4–7) 5 (1, 4–5)
SOFA score at baseline 10 (7, 5–21) 11 (7, 6–21)
APACHE II score 23 (13, 8–29) 24 (11, 9–29)
Child–Pugh classification, n (%)
A; B; C 4 (23.5); 8 (47.1); 5 (29.4) 3 (25.0); 5 (41.7); 4 (33.3)
Demographic data
Sex, male/female, n/n 13/4 9/3
Age (years) 48 (31, 33–89) 51 (28, 33–72)
Actual body weight (kg) 58 (17, 48–87) 55 (14, 48–87)
Etiology, n (%)
Hepatocellular carcinoma 1 (5.9) 1 (8.3)
Chronic hepatitis B 2 (11.8) 2 (16.7)
Hepatitis B cirrhosis 2 (11.8) 1 (8.3)
Cholelithiasis 2 (11.8) 1 (8.3)
Transplanted 5 (29.4) 3 (25.0)
Sepsis-induced 3 (17.6) 2 (16.7)
Others 2 (11.8) 2 (16.7)
CYP2C19 genotype, n (%)a
*1/*1 5 (41.7) 3 (33.3)
*1/*2 5 (41.7) 5 (55.6)
*2/*2 1 (8.3) 0 (0.0)
*2/*3 1 (8.3) 1 (11.1)
Concomitant medication, n (%)
Esomeprazole 9 (52.9) 6 (50.0)
Pantoprazole 8 (47.1) 6 (50.0)
Biochemical indicesb
INR 1.39 (0.61, 1.05–2.36) 1.36 (0.36, 0.94–2.51)
ALT (U/l) 29 (63, 1–557) 18 (31, 2–250)
AST (U/l) 76 (90, 27–1322) 49 (67, 14–145)
TBIL (mmol/l) 132.6 (217.1, 9.9–439.5) 93.0 (253.3, 9.3–349.3)
ALB (g/l) 36.1 (11.0, 24.4–52.7) 34.6 (8.2, 28.8–45.5)
PLT (109/l) 62 (105, 14–424) 58 (133, 10–503)
SCr (mmol/l) 96 (96, 47–356) 75 (49, 57–305)

ALB, albumin; ALT, alanine aminotransferase; APACHE II score, Acute Physiology and Chronic Health Evaluation II score; AST, aspartate aminotransferase; C0, trough
concentration; INR, international normalized ratio; IQR, interquartile range; PK, pharmacokinetics; PLT, platelets; SCr, serum creatinine; SOFA score, sequential organ failure
assessment score; TBIL, total bilirubin.
a
Data are available for 12 patients because CYP2C19 genotyping was not performed for the other five patients with a history of liver transplantation.
b
Biochemical indices were measured on the day of sampling.

characteristics of intravenous VRC in different Child–Pugh classes Table 2

using non-compartmental analysis. PK parameters of intravenous voriconazole of PK curve 1 and PK curve 2; median
In the present study, a simple and reliable HPLC-MS/MS assay (IQR, range).
was developed to determine VRC plasma concentrations. Accord- PK parameters PK curve 1 (n = 17)a PK curve 2 (n = 12)
ing to the United States Food and Drug Administration bioanalyt-
t1/2 (h) 14.4 (12.4, 8.3–149.7) 31.3 (26.1, 5.9–180.0)
ical method validation guidance (U.S. Food and Drug Tmax (h) 1.01 (0.27, 0.75–1.20) 1.08 (0.16, 0.77–1.18)
Administration, 2001), this method is fully validated for specificity, Cmax (mg/ml) 4.90 (3.06, 1.92–9.12) 9.63 (3.11, 4.83–16.86)
linearity, precision, accuracy, recovery, matrix effect, and stability. Vss (l) 119.85 (91.29, 55.45– 112.57 (141.47, 52.35–
309.21) 554.97)
In some previously developed LC-MS/MS methods (Al-Ghobashy
CL (l/h) 5.09 (2.78, 0.60–9.57) 2.33 (1.13, 1.18–6.75)
et al., 2018; Prommas et al., 2017), fluconazole was used as the AUC0–12 (mg
h/ 26.55 (14.21, 13.20–49.06) 86.29 (34.88, 29.61–169.85)
internal standard. Considering that VRC might be used after ml)
fluconazole in clinical settings, we used deuterated VRC
AUC0–12, area under the concentration–time curve from 0 h to 12 h; CL, clearance;
(D3-voriconazole) as the internal standard, which eliminated Cmax, peak concentration; IQR, interquartile range; PK, pharmacokinetics; t1/2,
the interference of drugs including fluconazole on the detection of terminal half-life; Tmax, time to reach Cmax; Vss, apparent steady-state volume of
the internal standard. The adopted method was validated to be distribution.
a
Data on Tmax, Cmax, Vss, and AUC0–12 of PK curve 1 were available for 16 patients;
accurate and precise, with high extraction recovery and no matrix
data for patient 14 were not included, because Cmax was not obtained for this
effect, and can be applied to clinical TDM for VRC. patient.
The estimated median CL (2.33 l/h) of PK curve 2 in the present
study is lower than the values reported in several studies that were corresponding Cmax (r2 = 0.963), indicating that both C0 and Cmax
not focused on patients with liver dysfunction (4.28–6.95 l/h) are good surrogates for measuring VRC plasma exposure (AUC). In
(Chen et al., 2015; Pascual et al., 2012; Wang et al., 2014a). the current study, the first C0 determined on day 5 (median) was as
Moreover, the t1/2 of PK curve 2 was 31.3 h (median), which is high as 5.27 (2.61) mg/ml; only two C0 values were less than the
substantially longer than that of healthy volunteers (6 h) reported lower target of the therapeutic window (2–6 mg/ml), but 29.4%
in the early PK studies (Jeu et al., 2003). Consistent with previous (5/17) exceeded the upper limit of 6 mg/ml. Similarly, under a
findings (Chen et al., 2015; Han et al., 2010; Johnson et al., 2010; standard VRC maintenance dose of 200 mg twice daily, a high C0
Wang et al., 2015), there was a close correlation between AUC0–12 was also observed in patients with liver dysfunction by Gao et al.
and the corresponding C0 (r2 = 0.951) in the present study. We also (Gao et al., 2018) and Wang et al. (Wang et al., 2018b). These results
found that AUC0–12 was significantly correlated with the indicate that decreased liver function could substantially reduce
 X.- Lin et al. / International Journal of Infectious Diseases 93 (2020) 345–352 349

Table 3
PK parameters of intravenous voriconazole of PK curve 1 and PK curve 2 in the different Child–Pugh classes; median (IQR).

PK parameters PK curve 1 (n = 17), Child–Pugh class PK curve 2 (n = 12), Child–Pugh class

a
A (n = 4) B (n = 8) C (n = 5) A (n = 3) B (n = 5) C (n = 4)
t1/2 (h) 12.6 (5.3) 20.7 (12.3) 14.5 (85.5) 24.4 (NA) 29.1 (20.4) 60.7 (129.4)
Tmax (h) 1.00 (NA) 1.02 (0.21) 0.78 (0.25) 1.08 (NA) 1.00 (0.28) 1.15 (0.13)
Cmax (mg/ml) 5.79 (NA) 4.36 (2.18) 6.64 (5.41) 7.76 (NA) 9.13 (3.98) 10.22 (5.64)
Vss (l) 85.58 (NA) 129.40 (83.16) 99.65 (150.89) 83.42 (NA) 124.89 (55.60) 159.16 (414.65)
CL (l/h) 8.60 (4.13) 5.21 (2.13) 4.72 (3.37) 3.31 (NA) 2.54 (1.06) 2.04 (0.77)
AUC0–12 (mg
h/ml) 24.91 (NA) 23.37 (12.99) 28.60 (20.25) 60.45 (NA) 78.83 (35.62) 98.04 (59.48)

AUC0–12, area under the concentration–time curve from 0 h to 12 h; CL, clearance; Cmax, peak concentration; IQR, interquartile range; NA, not available; PK, pharmacokinetics;
t1/2, terminal half-life; Tmax, time to reach Cmax; Vss, apparent steady-state volume of distribution.
a
Data on Tmax, Cmax, Vss, and AUC0–12 were available for three patients; data for patient 14 were not included, because Cmax was not obtained for this patient.

Figure 2. Correlations between AUC0–12 of PK curve 2 and the corresponding C0 and Cmax (n = 12). (A) AUC0–12 vs. C0. (B) AUC0–12 vs. Cmax. Abbreviations: AUC0–12, area under
the concentration–time curve from 0 h to 12 h; C0, trough concentration; Cmax, peak concentration; PK, pharmacokinetics.

Figure 3. Comparisons for the PK parameters (median) of PK curve 1 and PK curve 2 among Child-Pugh classes.(A) t1/2. (B) CL. (C) AUC0–12. Abbreviations: AUC0–12, area under
the concentration–time curve from 0 h to 12 h; C-P, Child-Pugh; CL, clearance; PK, pharmacokinetics; t1/2, terminal half-life.

VRC metabolism, resulting in a significant decrease in CL and a
significant prolongation of t1/2, ultimately leading to high plasma
exposure.
Although not all of the differences in PK parameters among the
three Child–Pugh classes were statistically significant due to the
limited sample size of this study, as the degree of hepatic
impairment increased (Child–Pugh class A < B < C), CL of VRC
decreased and t1/2 extended; as a result, AUC0–12 and the first C0
elevated. The CL (PK curve 2) of Child–Pugh class B and C patients
in our study were decreased to 2.54 and 2.04 l/h, respectively.
Recently, lower CL of 0.99 l/h in Child–Pugh class C cirrhotic
patients was reported in a retrospective study by Wang et al.
(Wang et al., 2019). In addition, t1/2 of Child–Pugh class C patients
in their study was extended to 111.7 h, which is nearly twice as long
as the value of 60.7 h (PK curve 2) estimated in our study.
Considering that elevated VRC exposure may increase the risk of
developing adverse reactions, dosing regimens should be adjusted
based on Child–Pugh classes for those ICU patients with liver
dysfunction.
Saturable metabolism leads to non-linear PK of VRC (Theur-
etzbacher et al., 2006). However, non-linear PK was not observed
in some studies, probably owing to the lack of intensive sampling
(Pascual et al., 2012; Wang et al., 2014a). In the present study, the
CL (median) of PK curve 2 was lower than that of PK curve 1 in all
three Child–Pugh classes, which could be attributed to the fact that
the largely decreased metabolism of VRC in patients with liver
dysfunction make it more susceptible to saturable metabolism. The
non-linear PK, one of the important sources for the wide individual
variability of VRC, would further complicate the optimal use of VRC
in patients with liver disease.
350 X.- Lin et al. / International Journal of Infectious Diseases 93 (2020) 345–352

It should be mentioned that CYP2C19 genotyping was

Figure 4. Distribution of the first C0 among Child-Pugh classes. The Bonferroni
correction was made for pairwise comparisons following the one-way ANOVA
(p = 0.032). Data are expressed as the median (interquartile range). Abbreviations:
C0, trough concentration; C-P, Child-Pugh.
As the actual body weight increased, Vss of PK curve 1 increased
(r2 = 0.707, n = 15) and AUC0–12 of PK curve 1 decreased (r2 = 0.614,
n = 16). This supports the intravenous administration of a loading
dose of VRC for adult ICU patients with liver dysfunction based on
their actual body weight. However, an actual body weight-adjusted
dosing regimen may not be feasible for obese patients, as this
would lead to high VRC concentrations (Davies-Vorbrodt et al.,
2013; Koselke et al., 2012). A dosing regimen based on adjusted
body weight has been proposed (Davies-Vorbrodt et al., 2013;
Koselke et al., 2012; Richards et al., 2017), and further studies are
needed. In the current study, no obese patient (body mass
index 30 kg/m2) was observed. The influence of obesity on the
PK of VRC in patients with liver dysfunction should be investigated
in the future. Additionally, t1/2 (PK curve 2) extended with elevated
INR (r2 = 0.510), and AUC0–12 (PK curve 2) increased with elevated
AST (r2 = 0.612) and TBIL (r2 = 0.515). These findings also reflect the
effect of liver function on the PK of VRC. Nevertheless, the
correlations between other PK parameters and indices of liver
function (including INR, AST, and TBIL) were significant but weak in
our study. Further research is required to identify the effects of
liver function indices on PK parameters of VRC for patients with
liver disease.
performed only for the 12 patients without a history of liver
transplantation. If the CYP2C19 genotypes differ between a donor
and a recipient, the expression level of CYP2C19 in liver graft tissue
depends on the donor (Chiu et al., 2015), indicating that the
CYP2C19 genotypes detected from peripheral blood of recipients
cannot replace the genotypes and phenotypes of CYP2C19 in the
liver graft. Therefore, CYP2C19 genotyping was not performed for
the patients with a history of liver transplantation (patients 4, 6, 7,
10, and 11) in our study. The distribution of CYP2C19 alleles varies
in different race/ethnic populations, including in the Asian
population (Zhou et al., 2019). The frequencies of CYP2C19*2, *3,
and *17 in East Asians are 28.4%, 7.3%, and 2.1%, respectively, but
those in Central/South Asians are 27.0%, 1.6%, and 17.1%,
respectively (PharmGKB). In addition, Chuwongwattana et al.
(Chuwongwattana et al., 2016) reported that the frequencies of
CYP2C19*2 and *3 in Thai patients were 25.7% and 4.8%,
respectively, but CYP2C19*17 was not found in their study. The
frequencies of CYP2C19*2 and *3 (33.3% and 4.2%, respectively) in
the 12 Chinese patients in our study were roughly in line with the
data for Chinese patients reported in several previous studies
(29.2–31.2% and 4.3–5.2%, respectively) (Lin et al., 2018; Miao et al.,
2019; Zhong et al., 2017; Zhuo et al., 2018). In a previous study, the
prevalences of CYP2C19*3 in Chinese liver transplant recipients and
donors were reported to be as high as 24.2% and 26.9%,
respectively, while no CYP2C19*2 was observed in either recipients
or donors (Zhu et al., 2016). This large difference in the distribution
of CYP2C19 alleles needs to be further studied.
In recent years, CYP2C19 polymorphisms have been identified to
be an important determinant of the wide PK variability of VRC (Lee
et al., 2012; Li et al., 2017; Lin et al., 2018; Wang et al., 2014a). The
loss-of-function alleles CYP2C19*2 and *3 have been associated
with increased C0 of VRC (Chuwongwattana et al., 2016;
Lamoureux et al., 2016). Several studies have found the CL of
VRC in poor metabolizers (CYP2C19*2/*2, *2/*3, *3/*3) to be low (Lin
et al., 2018; Wang et al., 2014a), resulting in significantly higher
plasma C0 compared with those in both intermediate metabolizers
(CYP2C19*1/*2, *1/*3) (Lin et al., 2018; Wang et al., 2014b) and
normal metabolizers (CYP2C19*1/*1) (Chuwongwattana et al.,
2016; Lin et al., 2018; Wang et al., 2014b). However, the effect of
CYP2C19 polymorphisms on the PK parameters of VRC was not
observed in patients with liver dysfunction by Tang et al. in their
recent retrospective study (Tang et al., 2019), and they attributed
the discrepancy to the decrease in activity of CYP450 enzymes. The
present study also did not find any significant associations
between the PK parameters and CYP2C19 genotypes (carrying at
least one deficient allele (*2 or *3) or not), but it should be
mentioned that a subgroup analysis in the different Child–Pugh
classes could not be performed to evaluate the effect of CYP2C19

Table 4
Correlations between PK parameters and the clinical characteristics and biochemical indices of the patients.

Variablesa First C0 (n = 17) PK curve 1 (n = 17) PK curve 2 (n = 12)

t1/2b CL AUC0–12c Vssc t1/2d CL AUC0–12 Vssd

Body weight 0.243 (+) 0.614 ( ) 0.450 (+)
INR 0.234 (+) 0.303 (+) 0.510 (+)
AST 0.355 (+) 0.361 ( ) 0.612 (+)
ALB 0.312 ( )
TBIL 0.312 (+) 0.307 ( ) 0.515 (+)

ALB, albumin; AST, aspartate aminotransferase; AUC0–12, area under the concentration–time curve from 0 h to 12 h; C0, trough concentration; CL, clearance; INR, international
normalized ratio; PK, pharmacokinetics; t1/2, terminal half-life; TBIL, total bilirubin; Vss, apparent steady-state volume of distribution.
a
Statistically significant r2 for simple linear regression between the two variables is shown, and symbols in parentheses indicate a positive (+) or negative ( ) association.
b
Analyses were available for 16 patients; data for patient 5 were excluded, because the t1/2 (149.7 h) of this patient was identified as an extreme outlier.
c
Analyses were available for 16 patients; data for patient 14 were not included, because Vss and AUC0–12 were not available for this patient.
d
Analyses were available for 11 patients; data for patient 3 were excluded, because both t1/2 (180.0 h) and Vss (554.97 l) of this patient were identified as extreme outliers.
 X.- Lin et al. / International Journal of Infectious Diseases 93 (2020) 345–352
Figure 5. Correlation between Vss of PK curve 1 and actual body weight. Main
figure, r2 = 45.0% when Vss and body weight were correlated for 16 patients. Inset,
r2 = 70.7% when Vss and body weightwere correlated for 15 patients, with an outlier
of Vss (309.21 l) from patient 3 omitted. Abbreviations: PK, pharmacokinetics; Vss,
apparent steady-state volume of distribution.
genotypes on PK parameters owing to the limited sample size, so
further studies are warranted.
All of the patients in the present study were co-administered
CYP2C19 inhibitor PPIs (esomeprazole or pantoprazole) during
VRC therapy. The effects of PPIs on VRC PK depend on the type of
PPI used (Qi et al., 2017; Yan et al., 2018; Yasu et al., 2016). Co-
administration with esomeprazole significantly increased VRC
plasma C0, whereas there was no significant correlation between
plasma C0 and the use of pantoprazole (Yan et al., 2018). In the
current study, it was difficult to compare the differences in PK
parameters between the co-administration of esomeprazole and
pantoprazole, since it was not possible to perform a subgroup
analysis due to the limited sample size. As the concomitant use of
the two drugs in the ICU is fairly common, the influence of PPIs on
VRC PK should be explored in patients with liver dysfunction.
The main limitation of this study is the small sample size, which
limited the power to evaluate the differences in PK parameters
among the different Child–Pugh classes. Secondly, data on CYP2C19
genotypes were only available for 12 patients, thus a subgroup
analysis could not be performed in our study. Therefore, further
investigations of the effects of CYP2C19 polymorphisms on the PK
of VRC in patients with hepatic impairment are required.
Additionally, dosing adjustment strategies could not be provided
in the current study due to the lack of data on plasma exposure
(AUC0–12 of PK curve 2) of patients with normal liver function for
comparison. Recommending adequate dosing regimens for ICU
patients with liver dysfunction is challenging and further studies
are needed. Despite the limitations, the present study may provide
a theoretical basis for the clinical use of VRC in ICU patients with
liver dysfunction and serve as a reference for further research.
In conclusion, the CL of VRC in patients with liver dysfunction
(especially Child–Pugh class C) largely decreased and t1/2 extended,
resulting in high plasma exposure. For these ICU patients, dosing
regimens of intravenous VRC should be adjusted based on Child–
Pugh classes, and plasma concentrations should be closely
monitored to avoid serious adverse events.
351
Author contributions
Study conception and design: Xiao Chen, Chang-jie Cai. Data
acquisition: Fa Huang, Li Tong, Yan-zhe Xia, Xiao-guang Hu. Data
analysis and interpretation: Xiao-bin Lin, Guo-ping Zhong.
Determination of plasma concentrations: Jing-jing Wu. DNA
extraction and detection: Jia Li, Tao Liang. Draft preparation:
Xiao-bin Lin, Fa Huang. Draft revision: Xiao-man Liu. Critical
review: All authors.
Funding
This work was supported by the National Key R&D Program of
China (No. 2017YFC0909904) and the Guangzhou Science and
Technology Program (No. 201704020153).
Ethical approval
This study was approved by the Ethics Committee of the First
Affiliated Hospital of Sun Yat-sen University (approval number 201848).
Conflict of interest
The authors declare that they have no conflict of interest.
Acknowledgements
We appreciate Jia-zhi Chen and Rui Dai for their assistance in
the collection of clinical data and blood samples.
Appendix A. Supplementary data
Supplementary material related to this article can be found, in
the online version, at doi:https://doi.org/10.1016/j.ijid.2020.02.041.
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