Voriconazole: A Review of Population Pharmacokinetic Analyses

Abstract

Numerous population pharmacokinetic studies on voriconazole have been conducted in recent years. This review aimed to comprehensively summarize the population pharmacokinetic models for voriconazole and to determine which covariates have been identified and which remain to be explored. We searched the PubMed and EMBASE databases from inception to March 2018 for population pharmacokinetic analyses of voriconazole using the nonlinear mixed-effect method. A total of 16 studies were included in this review, of which 11 models were described in adult populations, four were described in pediatric populations, and the remaining study included both adult and pediatric populations. The absorption profiles of voriconazole in both adult and pediatric studies were best described as first-order absorption models. The typical distribution volumes were similar in adult and pediatric patients, but the estimated clearances in pediatric patients were significantly higher than those in adult patients. The most commonly identified covariates were body weight, the cytochrome P450 2C19 genotype, liver function, and concomitant medications. Only one study evaluated the model using an external method. Further population pharmacokinetic studies on pediatric patients aged younger than 2 years are warranted. Furthermore, new or controversial potential covariates, such as inflammation, the cytochrome P450 3A4 genotype, concomitant medications (particularly various types and dosages of proton pump inhibitors and glucocorticoids), and various measures of body weight, should be tested because the unexplained variability remains relatively high. In addition, previously published models should be externally evaluated, and the predictive performance of the various models should be compared.

Saliva for Precision Dosing of Antifungal Drugs: Saliva Population PK Model for Voriconazole Based on a Systematic Review.

“…Therefore, inclusion of covariates would not have been highly informative. Previous plasma population models for voriconazole vary between the studies, in terms of PK compartments (one or two compartments), identified covariates, and PK parameter estimates (Shi et al, 2019). Amongst these studies, parameters from our study were comparable to those from Pascual et al (Pascual et al, 2012), who fitted a onecompartment model with the first-order absorption and first-order elimination to 505 plasma voriconazole concentrations from 55 adult patients.…”

“…cytochrome P450 2C19 genotype and liver function (e.g., ALT and AST) (Shi et al, 2019). Due to the high risk of selection bias, it is recommended to avoid stepwise covariate modeling for inclusion of statistically significant covariates in small data sets (<50-100 subjects), especially if the aim of the analysis is predictive modeling (Ribbing and Jonsson, 2004).…”

Impact of Albumin and Omeprazole on Steady-State Population Pharmacokinetics of Voriconazole and Development of a Voriconazole Dosing Optimization Model in Thai Patients with Hematologic Diseases

“…The mechanism behind the interaction with CYP450 inhibitors, omeprazole, and voriconazole is via CYP2C19 and CYP3A4 inhibitors [ 4 , 38 , 39 ]. On the one hand, the effect of PPIs on the PK of voriconazole depends on the dose and kind of PPIs, and how these factors affect various capabilities of CYP2C19 [ 12 , 36 ]. On the other hand, a recommendation specific to omeprazole 20 mg/day stated that this drug and dosage did not significantly affect voriconazole levels, which was similar to our study [ 4 , 40 ].…”

“…Voriconazole is mainly metabolized by CYP2C19 [ 4 , 11 ]. Therefore, high variability in the PK of voriconazole can be caused by CYP2C19 polymorphism [ 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 ], and these gene polymorphisms cause variations in drug clearance. Clinical factors that have been reported to affect the PK of voriconazole include body weight [ 15 , 16 , 20 , 22 , 23 ], age [ 18 , 19 ], liver function [ 20 ], aspartate aminotransferase (AST) [ 14 ], direct bilirubin (DB) [ 24 ], and voriconazole taken concurrently with CYP2C19 inducers (rifampin) [ 13 , 25 ], and inhibitors (proton pump inhibitors; PPIs) [ 17 ].…”

“…There is some evidence supporting the fact that low albumin levels can affect the plasma level of voriconazole [ 29 ]. However, there is no population PK study confirming this effect [ 12 ]. Population PK analysis is a strategy that can be employed to identify mean PK parameters and their variation, to identify significant covariates, and to establish the optimal dosage regimen of voriconazole [ 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 ].…”