4 Discussion
The factors affecting voriconazole Cmin and PPK date of
voriconazole in pediatric patients with hematologic malignancies are
limited. we investigated the factors affecting
voriconazole Cminand successfully developed a PPK model of voriconazole. Most notably,
the optimal regimes were recommended based on the final model.
Regarding the influencing factors of voriconazole Cmin,
as reported in adult patients with hematologic malignancies and other
pediatric patients24, 25, voriconazole exhibited a
non-linear pharmacokinetic profile. A report of adult
inpatients26 showed no difference in voriconazole
concentrations between intravenous and oral administration, which is
inconsistent with our results. Karin et al27 argued
that children have a greater metabolic capacity. Another possible
explanation is that patients with malignant hematological diseases are
prone to nausea and vomiting after chemotherapy. We also found a
negative correlation between ALB and voriconazole concentration as
reported by previous study28. Accordingly, we should
be more alert to the effect of ALB levels on voriconazole
concentrations, especially in patients with low serum albumin. In terms
of concomitant administration, the results of this study showed that
combination with PPIs resulted in higher concentrations while
Co-administration of GLU resulted in lower concentrations, which is in
line with previous studies29, 30. Some studies have
documented that gender31, SCR32,
liver function indicators (ALP, AST, ALT, etc.)28, 33and CRP levels34, 35 could affect voriconazole
concentrations. However, no significant correlation between these
factors and voriconazole concentration were found in this study. The
explanation for this may be the difference of race, age and population
and further investigation are necessary in the future.
In the part of PPK analysis, the results show that a one-compartment
model fits the data best. However, the other studies of children were
two-compartment models36-38, probably due to the fact
that pediatric studies are mainly preclinical studies and multicenter
large sample studies with a dense sampling strategy, while the sampling
strategy of this study was sparse. Fortunately, Farkas et
al.39 compared the accuracy and precision of
voriconazole linear, nonlinear, and mixed linear models for prediction.
The results suggested that the linear model was slightly more accurate
than the other two models, but the differences were minor from a
clinical point of view, making all three models suitable for
voriconazole.
As summarized in a review of PPK of voriconazole40,
the median of central compartment volume of distribution
(VC) was 1.07 L/kg (0.81-3.26 L/kg), and the
interindividual variability of V or V1 and
CL was 14.2% (13.6 to 45.4%) and
69.6% (66.5% to 117.4%). These shows that the pharmacokinetic
parameters of voriconazole vary significantly among the different
pediatric populations, further demonstrating the necessity for
individualized dosage in pediatric populations with hematologic
malignancies. The population typical values of CL of voriconazole in
another pediatric one-compartment model were 2.94 L/h and the apparent
volume of distribution was 6.17 L and 7.67 L.40However, the typical values of CL and V in this study were only 1.52 L/h
and 35.7 L. The possible reasons are as follows: the patients included
in this study are patients with hematologic malignancies, who had
different degrees of thrombocytopenia and liver dysfunction due to
myelosuppression after receiving chemotherapy. However, several studies
demonstrated that the reduction of voriconazole elimination is
significantly related to liver function16, 41. It was
also documented in the previous studies that platelet counts were
associated with the severity of liver function, where the CL was only
0.88 L/h and 0.58 L/h12, 42.
The oral bioavailability in this study is 90.9%, higher than 44.6%
~ 73% in other study of children,22,
23, 43, 44 but lower than 96% and 94.2% in adult.45,
46 Numerous literatures reported that the oral bioavailability is
affected by CYP2C19 genotype, dose, adverse reactions of chemotherapy,
such as nausea and vomiting, disease status, gastrointestinal function
and diet.45, 47, 48 A study written by Scholz et
al48 indicated that after intravenous and oral
administration of 400 mg voriconazole, the bioavailability of PM was
94.4% (78.8%, 109.9%), while EM was 75.2% (62.9,87.4%). Most
notably, the proportion of PM patients in this study is 14.3%, which is
much larger than that in Japan and Europe by 2.0% ~
9.5%.49, 50 Besides, the bioavailability of 50 mg and
400 mg voriconazole was 39% and 86% respectively from the study by
Hohmann et al6. These may be the reason why the oral
bioavailability of this study is higher than that of other children’s
studies.
The covariates included in the final model of previous pediatric PPK
studies22, 49, 50 were body weight, CYP2C19 genotypes
and ALT. In contrast, the EM and ALB were the significant covariates for
the CL of voriconazole, and there were no covariates that had a
significant effect on V in the present work. The results of adults with
hematological malignancies 19 showed that CYP2C19
genotype significantly affects CL of voriconazole and
AUC0-12h of PM is 2.5 and 1.8 times of EM and IM
respectively. In this study, the CL of voriconazole in children with
non-EM is reduced by 29.6% compared with EM, which is similar to the
35.5% of another pediatric study.50 The Wei et
al51 study showed that Low ALB level is significantly
correlated with the blood concentration of voriconazole >
5.5 mg/L. Moreover, the study conducted by Dote et
al52 showed that hypoproteinemia (ALB < 30
g/L) is associated with the low CL of voriconazole. Therefore, attention
should be paid to monitoring voriconazole blood concentrations in
patients with low protein levels and to developing individualized dosing
regimens based on ALB levels in conjunction with PPK models to improve
treatment efficacy and reduce adverse effects associated with increased
blood concentrations.
Currently, there is no recommendation of individualized drug
administration for children with hematologic malignancy. In the present
study, the dosing was simulated according to CYP2C19 genotype and ALB
level. The recommended doses (mg/kg) were4, 8 and 12 mg/kg intravenously
o orally twice daily for ALB levels of 20.0~35.0 g/L,
35.1~45.0 g/L and 45.1~55.0 g/L for
patients with EM, and were 2, 4 and 7 mg/kg intravenously or orally
twice daily for patients with non-EM. The results indicate that higher
dose (mg/kg) should be recommended for extensive metabolizer, which is
similar to the study of Lin et al53. Besides, as
described by Prawat et al54, patents with lower ALB
levels were more likely to achieve the target trough concentration.
Nevertheless, when the ALB level of EM is 45.1 ~ 55.0
g/L, the proportion of the concentration < 0.5 mg/L is still
high even if the dosage reaches 12 mg/kg in oral or intravenous
administration. Hence, whether such patients choose to give high-dose
voriconazole or switch to other antifungal drugs in clinical medication
remains to be further considered for its efficacy and safety. Overall,
the recommended regimen significantly improved the probability of
reaching the target trough
concentration of 0.5 – 5 mg/L and
minimized the probability of the concentration < 0.5 mg/L and
> 5 mg/L, which could maximize the efficacy and minimize
the adverse reactions of voriconazole in the treatment process.
This study has several limitations: Firstly, due to the limitations of
clinical sampling and testing techniques, only a few patients had MIC
values, and it was not possible to combine PK/PD parameters AUC0-24h/MIC
for dosing regimen development. Secondly, the effects CYP2C9 and CYP3A4
genotype on the pharmacokinetic parameters of voriconazole were not
investigated. Finally, this study was a single-center study, whether the
findings are applicable to other centers needs to be verified in the
future.