Predictive Value of C‐Reactive Protein and Albumin for Temporal Within‐Individual Pharmacokinetic Variability of Voriconazole in Pediatric Patients Undergoing Hematopoietic Cell Transplantation

Abstract

Voriconazole is a widely used antifungal agent in immunocompromised patients, but its utility is limited by its variable exposure and narrow therapeutic index. Population pharmacokinetic (PK) models have been used to characterize voriconazole PK and derive individualized dosing regimens. However, determinants of temporal within-patient variability of voriconazole PK were not well established. We aimed to characterize temporal variability of voriconazole PK within individuals and identify predictive clinical factors. This study was conducted as a part of a single-institution, phase I study of intravenous voriconazole in children undergoing hematopoietic cell transplantation (NCT02227797). We analyzed voriconazole PK study data collected at week 1 and again at week 2 after the start of voriconazole therapy in 59 pediatric patients undergoing HCT (age <21 years). Population PK analysis using nonlinear mixed effect modeling was performed to analyze temporal within-individual variability of voriconazole PK by incorporating a between-occasion variability term in the model. A 2-compartment linear elimination model incorporating body weight and cytochrome P450 2C19 phenotype described the data. The ratio of individual voriconazole clearance between weeks 1 and 2 ranged from 0.11 to 3.3 (−9.1 to +3.3-fold change). Incorporation of covariate effects by serum C-reactive protein and albumin levels decreased between-occasion variability of clearance as compared to the model without them (coefficient of variation, 41.2% and 59.5%, respectively) and improved the model fit (P < .05). As significant covariates on voriconazole PK, C-reactive protein and albumin concentrations may potentially serve as useful biomarkers as part of therapeutic drug monitoring.

Dosage optimization of voriconazole in children with haematological malignancies based on population pharmacokinetics

“…Other variables, such as ALT, ALP, and glucocorticoids, were found to be significant covariates in other studies and were excluded from our study owing to minor variations in OFV (∆OFV < 3.84) 34,36,39 . ALB was the significant covariate for the CL of voriconazole, which was consistent with the previous studies 17,18,40 . Wei et al 41 showed that low ALB levels significantly correlated with the supratherapeutic voriconazole Cmin.…”

“…The IIV of the CL in this study was 57%, which were lower than those of other paediatric studies (66.5%–117.4%) 30 . The RSV was 41.7%, similar to other studies (20.2%–58.2%) 18,23,27,28 . In addition, the shrinkage values of IIV and RSV were 7.65% and 13.98%, respectively, both below 20%, indicating that the model is stable.…”

“…30 The RSV was 41.7%, similar to other studies (20.2%-58.2%). 18,23,27,28 In addition, the shrinkage values of IIV and RSV were 7.65% and 13.98%, respectively, both below 20%, indicating that the model is stable.…”

“…To date, there are several voriconazole PPK models of haematological malignancies that have been published. 16,17 Meanwhile, Takahashi et al 18 have recently published a PPK model in paediatric patients with haematological malignancies. However, the race could also cause the PK parameters to be different.…”

Population pharmacokinetics of voriconazole and initial dosage optimization in patients with talaromycosis

“…Hypoalbuminemia is also one of significant characteristics in these patients, which likely to have been caused by an imbalance between ALB synthesis and catabolic rate, and secondary to an active inflammation ( Chantharit et al, 2020 ). Hypoalbuminemia increases VRC plasma unbound drug concentration which may lead to drug-related adverse reactions ( Khan-Asa et al, 2020 ; Yuan et al, 2020 ; Takahashi et al, 2021 ). In this study, hypoalbuminemia did not show to be a significant covariate of VRC plasma exposure.…”