Population pharmacokinetics of voriconazole and CYP2C19 polymorphisms for optimizing dosing regimens in renal transplant recipients

Abstract

Using a combination of CYP2C19 genotype and postoperative time to determine the initial voriconazole dosing regimens followed by therapeutic drug monitoring could help to advance individualized treatment in renal transplantation patients with invasive fungal infections.

Voriconazole: A Review of Population Pharmacokinetic Analyses

“…The initial database search yielded 152 publications, and after selection, a total of 16 studies involving 1411 participants met the inclusion criteria [11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26]. The population characteristics of the included studies are summarized in Table 1.…”

“…CYP 2C19 genotyping data were included in 11 articles [12, 14-18, 21, 23-26]. Among the 16 publications describing a population pharmacokinetic model for voriconazole, 11 described studies conducted in adult participants, [11][12][13][14][15][16][17][18][19][20][21] whereas four of the studies were conducted in pediatric populations, [22][23][24][25] and the remaining study by Friberg et al [26] included both adult and pediatric patients. The studied populations consisted of healthy volunteers and patients who were administered voriconazole for the treatment or prophylaxis of fungal infections, possibly accompanied by additional pathologies, including pulmonary diseases, organ transplant, and hematological malignancies.…”

“…In addition, 56% of the studies involved rich data, and only two studies [15,18] involved sparse data from routine TDM practice. Almost all the included studies utilized the gold-standard software NONMEM to construct a population pharmacokinetic model with the exception of two studies, which used Phoenix NLME software [15,16]. All the models were validated using various advanced internal methods, including bootstrap, [11, 13-16, 18-21, 26] visual predictive check or corrected visual predictive check, [11,12,14,17,22,24,26] case deletion diagnostics, [23] and cross-validation [25].…”

“…Only one study performed an external evaluation using a separate cohort [14]. Simulation analyses were also performed in ten studies to determine the optimal dosing regimens [11,13,16,[18][19][20][21][22][23]26]. The majority of the studies adopted the trough concentration as the target, and the remaining studies chose the free area under the plasma concentration-time curve from 0 to 24 h divided by the minimum inhibitory concentration, trough concentration/ minimum inhibitory concentration, and the reference adult area under the plasma concentration-time curve distribution.…”

Identifying factors affecting the pharmacokinetics of voriconazole in patients with liver dysfunction: A population pharmacokinetic approach

“…Studies have found that CYP2C19 polymorphisms extensively affected voriconazole plasma concentration. 14,19,[48][49][50][51] A recent prospective study in renal transplant recipients 52 showed that CYP2C19 polymorphisms significantly affected the CL of voriconazole; PM patients had significantly higher plasma concentration than both IM patients and EM patients. However, CYP2C19 polymorphisms, it did not affect the pharmacokinetic parameters of voriconazole in this study.…”