Population Pharmacokinetic Analysis of Voriconazole from a Pharmacokinetic Study with Immunocompromised Japanese Pediatric Subjects

Abstract

A population pharmacokinetic (PK) analysis was conducted to characterize the voriconazole pharmacokinetic profiles in immunocompromised Japanese pediatric subjects and to compare them to those in immunocompromised non-Japanese pediatric subjects. A previously developed two-compartment pharmacokinetic model with first-order absorption and mixed linear and nonlinear elimination adequately described the voriconazole intravenous and oral data from Japanese pediatric subjects with few modifications. Bayesian priors were applied to this analysis by using the NONMEM routine NWPRI, which allowed priors for the fixed-effect parameter vector and variance matrix of the random-effect parameters to be a normal distribution and an inverse Wishart distribution, respectively. Large intersubject variabilities in oral bioavailability and voriconazole exposure were observed in these pediatric subjects. The mean oral bioavailability estimated in Japanese pediatric subjects was 73% (range, 17% to 99%), which is consistent with the reported estimates of 64% in the previous model and less than what was originally estimated for healthy adults-96%. Voriconazole exposures in Japanese pediatric subjects were generally comparable to those in non-Japanese pediatric subjects receiving the same dosing regimens, given the large intersubject variability. Consistent with the previous findings, the CYP2C19 genotyping status did not have a clinically relevant effect on voriconazole exposure in Japanese pediatric subjects, although it was identified as a covariate in the model to help explain the intersubject variability in voriconazole exposure. The CYP2C19 genotyping status alone does not warrant dose adjustment of voriconazole. No other factors besides age and weight were identified to explain the PK variability of voriconazole. Voriconazole is a broad-spectrum triazole antifungal agent for the treatment of patients with opportunistic fungal infections, such as invasive aspergillosis (1). It exhibits potent and wide-ranging in vitro activity, including fungicidal activity against Aspergillus species and other fungi. Immunocompromised children, particularly those with hematological malignancies, are at higher risk for systemic fungal infections, which significantly affect the prognosis of such patients. Voriconazole is suggested as a treatment option for fungal infections in children in Japanese and overseas guidelines.Voriconazole is extensively metabolized by and is also an inhibitor of the cytochrome P450 (CYP) isozymes CYP2C19 (major), CYP2C9, and CYP3A4 (2), which results in extensive drug interactions with concomitant medications. Voriconazole exhibits nonlinear pharmacokinetics (PK), and intersubject variability in voriconazole exposure is high. It has been demonstrated that in healthy adults CYP2C19 genotype, gender, and age are key factors that help explain this variability (3). CYP2C19 exhibits genetic polymorphism, and approximately 3% to 5% of Caucasians and African Americans and up to 20% of Asians are poor metabolizers (PMs) (4, 5)....

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.…”

“…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].…”

“…The absorption characteristics of voriconazole were described as a firstorder process in 13 of the included studies [12-18, 20-24, 26]. The absorption rate constant was fixed to the literature value in six studies [15-18, 21, 22], and a lag time was used [12,14,17,24,26] to characterize delayed absorption. The typical oral bioavailability of voriconazole reportedly ranged from 45.9% to 94.2% in adult patients (n = 6) and from 44.6% to 64.5% in pediatric populations (n = 4).…”

“…All of the studies conducted in pediatric populations employed a two-compartment model with various types of elimination, including linear, [25] nonlinear, [22,23] and mixed linear and nonlinear elimination [24,26]. The median (range) estimated values for the central distribution volume (…”