Pharmacokinetics and Safety of Voriconazole Intravenous-to-Oral Switch Regimens in Immunocompromised Japanese Pediatric Patients

Abstract

The aim of this study was to investigate the pharmacokinetics, safety, and tolerability of voriconazole following intravenous-tooral switch regimens used with immunocompromised Japanese pediatric subjects (age 2 to <15 years) at high risk for systemic fungal infection. Twenty-one patients received intravenous-to-oral switch regimens based on a recent population pharmacokinetic modeling; they were given 9 mg/kg of body weight followed by 8 mg/kg of intravenous (i.v.) voriconazole every 12 h (q12h), and 9 mg/kg (maximum, 350 mg) of oral voriconazole q12h (for patients age 2 to <12 or 12 to <15 years and <50 kg) or 6 mg/kg followed by 4 mg/kg of i.v. voriconazole q12h and 200 mg of oral voriconazole q12h (for patients age 12 to <15 years and >50 kg). The steady-state area under the curve over the 12-h dosing interval (AUC 0 -12,ss ) was calculated using the noncompartmental method and compared with the predicted exposures in Western pediatric subjects based on the abovementioned modeling. The geometric mean (coefficient of variation) AUC 0 -12,ss values for the intravenous and oral regimens were 51.1 g · h/ml (68%) and 45.8 g · h/ml (90%), respectively; there was a high correlation between AUC 0 -12,ss and trough concentration. Although the average exposures were higher in the Japanese patients than those in the Western pediatric subjects, the overall voriconazole exposures were comparable between these two groups due to large interindividual variability. The exposures in the 2 cytochrome P450 2C19 poor metabolizers were among the highest. Voriconazole was well tolerated. The most common treatment-related adverse events were photophobia and abnormal hepatic function. These recommended doses derived from the modeling appear to be appropriate for Japanese pediatric patients, showing no additional safety risks compared to those with adult patients. (This study has been registered at ClinicalTrials.gov under registration no. NCT01383993.) V oriconazole is a triazole antifungal drug that has been recommended in guidelines for the treatment of invasive fungal infections in adults in Japan (1) and the rest of the world (2-5). A 2009 nationwide survey regarding treatment for pediatric patients with invasive fungal infections in Japan found that antifungal agents not approved for pediatric use, including voriconazole, were frequently being used in clinical practice at a wide range of doses (6).Voriconazole is metabolized by the human hepatic cytochrome P450 enzymes, primarily CYP2C19 but also CYP3A4 and, to a lesser extent, CYP2C9, to its main circulating N-oxide metabolite (UK-121,265) (7, 8), with a significantly faster clearance of voriconazole in children than that in adults (9, 10). The CYP2C19 enzyme exhibits genetic polymorphisms, and the CYP2C19 genotype can be a key factor in the pharmacokinetics of voriconazole in individual patients. A marked interethnic difference in the frequency of CYP2C19 poor metabolizers (PM) has been noted (11). The frequencies of CYP2C19 PM have been estimated at 2.2% of Caucasian compare...

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

“…There was good correlation between the estimated voriconazole AUC 12 and C min in this analysis (Fig. 3), which is consistent with the noncompartmental analysis results (7).…”

“…As with adults, dose adjustment can be made subsequently based on the pediatric patient's clinical response and the tolerability and/or voriconazole trough concentrations (if available). Detailed justification of the appropriateness of these dosing regimens as the initial recommendation for pediatric patients and discussion on how to use therapeutic drug monitoring as an additional tool to facilitate voriconazole management have been published elsewhere (7).…”

“…An exploratory analysis of the effect of CYP2C19 genetic polymorphisms and predicted metabolic enzyme activity on voriconazole plasma concentrations was performed in this study. The voriconazole exposure results based on the noncompartmental analysis method and the safety results from the study have been published elsewhere (7).…”

“…Due to limited experience with and safety information on the proposed dosing regimens of voriconazole in Japanese children, an additional PK study was conducted to evaluate optimal doses of voriconazole in Japanese pediatric subjects (7). An exploratory analysis of the effect of CYP2C19 genetic polymorphisms and predicted metabolic enzyme activity on voriconazole plasma concentrations was performed in this study.…”

Pharmacodynamic studies of voriconazole: informing the clinical management of invasive fungal infections

“…Some have hypothesized that this is the reason for variability in absorption in children since they are much less likely to be taking the medication in the fasting state [50]. Ironically a Japanese study could not demonstrate the decreased absorption and saw 90% absorption in their study, suggesting that it may be due to the effect of administration in the non-fasted state [51]. Reports of voriconazole protein binding range between 48-60%, allowing high tissue penetration [52][53][54] and central nervous system distribution [54,55].…”