Population pharmacokinetics, safety and dosing optimization of voriconazole in patients with liver dysfunction: A prospective observational study

Tang, Dan; Yan, Miao; Song, Bingbing; Zhao, Yang; Xiao, Yiwen; Wang, Feng; Liang, Wu; Zhang, Bikui; Chen, Xi‐jing; Zou, Jianjun; Tian, Yi; Wen-long, Wang; Jiang, Yongfang; Gong, Guozhong; Zhang, Min; Xiang, Da‐Xiong

doi:10.1111/bcp.14578

Cited by 29 publications

(39 citation statements)

References 43 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…A PPK analysis of patients with liver cirrhosis found that CYP2C19 genotypes strongly affected the CL of VRC 26 . However, the significant effect of CYP2C19 genotypes on the PK parameters of VRC in patients with liver dysfunction was not observed in two other PPK studies 25,34 . Similarly, the CYP2C19 phenotype (IM/PM vs. NM) was not identified as a significant covariate in the present study.…”

Section: Discussioncontrasting

confidence: 75%

“…However, dosing simulations in our present study showed that the intravenous VRC loading dose of 5 mg/kg q12h was adequate for Child‐Pugh class A/B and C patients to attain the C min target at 24 h with high probabilities (87.9% and 94.0%, respectively). Similarly, a lower loading dose of 200 mg q12h intravenously or orally was recommended for liver cirrhotic patients 24 and for total bilirubin (TBIL) −2 (51 μmol/L ≤ TBIL <171 μmol/L) and TBIL‐3 (TBIL ≥171 μmol/L) patients 25 . These studies indicated that patients with liver dysfunction required a reduced loading dose of intravenous VRC.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Population pharmacokinetic model‐guided optimization of intravenous voriconazole dosing regimens in critically ill patients with liver dysfunction

et al. 2021

View full text Add to dashboard Cite

Study Objectives This study aimed to establish a population pharmacokinetic (PPK) model of intravenous voriconazole (VRC) in critically ill patients with liver dysfunction and to explore the optimal dosing strategies in specific clinical scenarios for invasive fungal infections (IFIs) caused by common Aspergillus and Candida species. Design Prospective pharmacokinetics study. Setting The intensive care unit in a tertiary‐care medical center. Patients A total of 297 plasma VRC concentrations from 26 critically ill patients with liver dysfunction were included in the PPK analysis. Methods Model‐based simulations with therapeutic range of 2–6 mg/L as the plasma trough concentration (Cmin) target and the free area under the concentration‐time curve from 0 to 24 h (ƒAUC24) divided by the minimum inhibitory concentration (MIC) (ie, ƒAUC24/MIC) ≥25 as the effective target were performed to optimize VRC dosing regimens for Child‐Pugh class A and B (CP‐A/B) and Child‐Pugh class C (CP‐C) patients. Results A two‐compartment model with first‐order elimination adequately described the data. Significant covariates in the final model were body weight on both central and peripheral distribution volume and Child‐Pugh class on clearance. Intravenous VRC loading dose of 5 mg/kg every 12 h (q12h) for the first day was adequate for CP‐A/B and CP‐C patients to attain the Cmin target at 24 h. The maintenance dose regimens of 100 mg q12h or 200 mg q24h for CP‐A/B patients and 50 mg q12h or 100 mg q24h for CP‐C patients could obtain the probability of effective target attainment of >90% at an MIC ≤0.5 mg/L and achieve the cumulative fraction of response of >90% against C. albicans, C. parapsilosis, C. glabrata, C. krusei, A. fumigatus, and A. flavus. Additionally, the daily VRC doses could be increased by 50 mg for CP‐A/B and CP‐C patients at an MIC of 1 mg/L, with plasma Cmin monitored closely to avoid serious adverse events. It is recommended that an appropriate alternative antifungal agent or a combination therapy could be adopted when an MIC ≥2 mg/L is reported, or when the infection is caused by C. tropicalis but the MIC value is not available. Conclusions For critically ill patients with liver dysfunction, the loading dose of intravenous VRC should be reduced to 5 mg/kg q12h. Additionally, based on the types of fungal pathogens and their susceptibility to VRC, the adjusted maintenance dose regimens with lower doses or longer dosing intervals should be considered for CP‐A/B and CP‐C patients.

show abstract

Section: Discussioncontrasting

confidence: 75%

Section: Discussionmentioning

confidence: 99%

Population pharmacokinetic model‐guided optimization of intravenous voriconazole dosing regimens in critically ill patients with liver dysfunction

et al. 2021

View full text Add to dashboard Cite

show abstract

“…Voriconazole displays non-linear pharmacokinetic (PK) in adults and manifests extreme inter- and intra-individual PK variability in all patient populations, which are also associated with liver dysfunction, drug–drug interaction, etc. [ 18 , 19 , 20 , 21 ]. Although under the standard administration scheme, the voriconazole trough concentration [ 18 ], related to clinical efficacy, is distributed in the range of less than 0.2 mg/L to 12 mg/L, even exceptionally high (17.5 mg/L), leading to adverse reactions [ 22 , 23 ].…”

Section: Introductionmentioning

confidence: 99%

Predictors of Voriconazole Trough Concentrations in Patients with Child–Pugh Class C Cirrhosis: A Prospective Study

et al. 2021

Self Cite

View full text Add to dashboard Cite

This prospective observational study aimed to clinically describe voriconazole administrations and trough concentrations in patients with Child–Pugh class C and to investigate the variability of trough concentration. A total of 144 voriconazole trough concentrations from 43 Child–Pugh class C patients were analyzed. The majority of patients (62.8%) received adjustments. The repeated measured trough concentration was higher than the first and final ones generally (median, 4.33 vs. 2.99, 3.90 mg/L). Eight patients with ideal initial concentrations later got supratherapeutic with no adjusted daily dose, implying accumulation. There was a significant difference in concentrations among the six groups by daily dose (p = 0.006). The bivariate correlation analysis showed that sex, CYP2C19 genotyping, daily dose, prothrombin time activity, international normalized ratio, platelet, and Model for end-stage liver disease score were significant factors for concentration. Subsequently, the first four factors mentioned above entered into a stepwise multiple linear regression model (variance inflation factor <5), implying that CYP2C19 testing makes sense for precision medicine of Child–Pugh class C cirrhosis patients. The equation fits well and explains the 34.8% variety of concentrations (R2 = 0.348). In conclusion, it needs more cautious administration clinically due to no recommendation for Child–Pugh class C patients in the medication label. The adjustment of the administration regimen should be mainly based on the results of repeated therapeutic drug monitoring.

show abstract

“…VRCZ is mainly metabolised by CYP2C19 5. Liver dysfunction can reduce the plasma clearance of drugs because of the decrease in hepatic metabolism capacity or biliary excretion 6. Meanwhile, multiple factors are already known to be associated with variability in VRCZ serum concentrations including age, sex, weight and genetic polymorphism of the CYP2C19 enzyme,7–10 and create a challenge for clinicians to optimise VRCZ dosing regimens 11.…”

Section: Introductionmentioning

confidence: 99%

“…Meanwhile, multiple factors are already known to be associated with variability in VRCZ serum concentrations including age, sex, weight and genetic polymorphism of the CYP2C19 enzyme,7–10 and create a challenge for clinicians to optimise VRCZ dosing regimens 11. Hence, a number of studies have shown that therapeutic drug monitoring is useful in adjusting individualised dosing based on VRCZ plasma concentrations 5 6 12…”

Section: Introductionmentioning

confidence: 99%

Factors affecting voriconazole concentration to dose ratio changes according to route of administration

Chen

Zhou

et al. 2022

Eur J Hosp Pharm

View full text Add to dashboard Cite

BackgroundVoriconazole (VRCZ) is commonly used as oral and intravenous (IV) formulations. Few studies have comprehensively analysed the variation factors for the weight-corrected VRCZ serum concentration/dose (C/D) ratio based on the administration route. We retrospectively investigated the risk factors that influence the VRCZ C/D ratio in patients treated with oral or IV formulations.MethodsA total of 325 patients were divided into two groups (IV and oral groups). Propensity score matching was performed and linear regression analyses were used to identify the risk factors that affect the VRCZ C/D ratio according to the administration route. Receiver operating characteristic (ROC) curves were also used to assess the predictive potential for VRCZ trough concentration >5 µg/mL.ResultsThe VRCZ C/D ratio in the oral group was significantly lower than that in the IV group (p<0.001). Propensity score matching resulted in 65 in the IV group matched with 65 in the oral group. Multivariate analysis showed that age (p=0.039), aspartate aminotransferase (AST) (p=0.016) and total bilirubin (TBIL) (p=0.041) levels were independent influencing factors of the VRCZ C/D ratio in the oral group. ROC curves showed that the predicted probability of combined age, AST and TBIL had maximal area under the curve (AUC) of 0.901 for VRCZ trough level >5 µg/mL. Meanwhile, the ratio of TBIL (p=0.005) and single dose (p=0.015) were independent factors in the IV group with ROCAUC of 0.781.ConclusionsTo obtain optimal VRCZ efficacy and safety, dose adjustment is required based on multiple factors that may cause the observed difference in the VRCZ C/D ratio and trough levels between oral and IV administration.

show abstract

Population pharmacokinetics, safety and dosing optimization of voriconazole in patients with liver dysfunction: A prospective observational study

Cited by 29 publications

References 43 publications

Population pharmacokinetic model‐guided optimization of intravenous voriconazole dosing regimens in critically ill patients with liver dysfunction

Population pharmacokinetic model‐guided optimization of intravenous voriconazole dosing regimens in critically ill patients with liver dysfunction

Predictors of Voriconazole Trough Concentrations in Patients with Child–Pugh Class C Cirrhosis: A Prospective Study

Factors affecting voriconazole concentration to dose ratio changes according to route of administration

Contact Info

Product

Resources

About