Hematological malignant tumor patients had a high-risk of fungal infection due to immunodeficiency and chemotherapy drugs. Voriconazole is increasingly used for the prevention and treatment of IFI. The population pharmacokinetic characteristics of voriconazole in children were more complicated14 and showed a large individual variation. Therefore, this retrospective study highlighted the reasons and factors affected VRC therapeutic trough concentration in children and discussed the dose adjustment strategy of voriconazole.
At the current maintenance dose for children younger than 12 years, voriconazole shows nonlinear pharmacokinetics15,16, warranting more cautious dose adjustment. Our study showed a large variability in voriconazole trough levels, with rate of 120.6% and 61.1% in inter-individual and intra-individual variability, similar to the published study17. More than 50% of children could not reach the target range (1.0-5.5µg/mL) at the initial trough concentration, which was consistent with many previous studies9,18, but was different with a European research6. The initial trough concentration in children aged 2–12 was significantly higher than that in children aged under 2 years, suggested a faster metabolism for infants. The EMA approved higher doses in 2 to 12 years old children, an 8 mg/kg intravenously twice daily (9 mg/kg day 1) or a 9 mg/kg orally twice daily. Our data suggested that underdose was so prevalent that 40.5% of children failed to reach the target concentration range and voriconazole dose was inadequate in this population. Lacking guidelines for dose recommendation of voriconazole in children, voriconazole maintenance doses vary widely in our center. As compared to the research of Karlsson MO et al7 and Neely M et al19 who illustrated VRC optimal dose of 7 mg/kg twice daily in children 2 to 12 years old, Shima H et al20 who recommended at least 8.5 mg/kg twice daily of VRC optimal dose for patients younger than 2 years, children with leukemia in our center might require higher doses and more frequent monitoring. The primary administration route of voriconazole in the present study was oral administration (88.3%) rather than the intravenous route recommended by the package insert for VRC. However, variability in oral bioavailability caused by meals and hepatic first-pass effect might associate with lower drug exposure3,21, which could be the reason for sub-therapeutic trough concentration.
Similar to that reported (7–10 days) in other centers19, the average time of the first TDM blood sampling in our hospital was 7 days (3.8-11days). In a randomized controlled trial22, the first TDM blood sampling was done on the fourth day after the initiation of voriconazole, which was calculated based on data from the literature so that it coincided with the target trough concentration range (1.0–5.5 mg/L). However, Miyakis S et.al23 showed that the initial trough concentrations of ≤ 0.35 µg/mL were significantly associated with increased mortality in pediatric with invasive candidiasis, so it was advised that the first steady-state TDM should be done ideally as early as possible (day 3 of therapy) to allow prompt dose adjustment. Our findings are consistent with previous study24, the co-administration of PPTs, mainly omeprazole, could significantly increase voriconazole plasma concentrations through CYP2C19 inhibition. However, in children the further exploration of the clinical implication of this drug interaction is absolutely imperative.
Another important factor affecting VRC therapeutic trough concentrations was polymorphism of CYP2C19. The CYP2C19 genotypic and phenotypic variability were extensive among different ethnic groups, but was controversial in relation to voriconazole treatment. Generally, the Caucasians or Africans have a lower proportion of PM metabolizers than Asians (2–5%, 6% and 13–23%, respectively). And for Caucasians and Africans, it is about 4 times more proportion in the Asian than them among the CYP2C19∗17 allele25–29. No CYP2C19*17 allele was found in our study. And EMs patients had a higher VRC trough concentrations and rate of VRC target concentrations. The above situation indicated that CYP2C19 genotype had a great influence on voriconazole metabolism in children, and the dose should be increased in EM patients. Hicks JK et al30 emphasized that a starting dose above 14 mg/kg/day could be recommended for all pediatric patients except for CYP2C19 extensive metabolizers. Based on age and CYP2C19 genotypes, VRC dose regime could be better determined and variation of drug trough concentrations could dramatically decrease. Therefore, available CYP2C19 genotype before the initial administration of voriconazole could improve the accuracy and safety of initial dosing31.
A guideline for VRC dose optimization is imperative in pediatric patients. A randomized controlled trial implemented by Park WB et al22 developed a dose adjustment strategy as following: increasing another 100% doses when the trough level was < 1.0 mg/L, on the contrary, reducing doses by 50% when the trough level was > 5.5 mg/L, but if there were adverse events, withholding voriconazole and reduce subsequent doses. However only 45.1% patients in 51 patients whose concentrations were not reach the target had the dose adjustment. And almost all the children younger than 2 failed to reach target concentration in the first TDM. Whether this optimized dosage strategy applicable to children ≤ 2 years old was unclear. Zembles TN et al32 had described their VRC optimized dosing strategy in three patients younger than 2 years and emphasized that a higher initial dose and perhaps 8 hours interval dosing schedule should be given to achieve VRC target therapeutic concentrations. Besides, Kendre'a M et al33 showed a regimen of 6 mg/kg, 3 times per day for intravenous and had proved its safety in a preterm infant younger than 3 months. Because voriconazole is not routinely monitored in children in our hospital, VRC trough concentration was seldom monitored again after adjusting dose. Finally, the dose-adjusted treatment response was significantly improved compared with the initial response. Pediatrician should recognize the importance of therapeutic drug monitoring of VRC and refer to the interpretation results of TDM conducted by clinical pharmacists in dosage adjustment.
Voriconazole, given orally or intravenously, is well tolerated in most of patients, with a rate of adverse reactions of 3.2%, which is much lower than previous reported (20.0%)18. Visual disturbances and photosensitive skin reactions were difficult to be detected and explained in pediatric may be one reason for that lower rate of adverse reactions.
Our study is a single-center retrospective study. There are a few limitations in study design and analysis. First, too small sample size restricts the difference significance analysis.
Second, no uniform guidelines and standardized protocol for VRC dose adjustment based on TDM data, resulting in a few confusions in doctors when adjusting doses.
Third, the number of CYP2C19
genotypic and phenotypic is too small to detect difference between trough concentration and genotypes.