Safety, Efficacy, and Exposure-Response of Voriconazole in Pediatric Patients With Invasive Aspergillosis, Invasive Candidiasis or Esophageal Candidiasis

Abstract

Background: Data on safety and efficacy of voriconazole for invasive aspergillosis (IA) and invasive candidiasis/esophageal candidiasis (IC/EC) in pediatric patients are limited.

Methods: Patients aged 2-<18 years with IA and IC/EC were enrolled in 2 prospective open-label, non-comparative studies of voriconazole. Patients followed dosing regimens based on age, weight and indication, with adjustments permitted. Treatment duration was 6-12 weeks for IA patients, ≥14 days after last positive Candida culture for IC patients and ≥7 days after signs/symptoms resolution for EC patients. Primary analysis for both the studies was safety and tolerability of voriconazole. Secondary end points included global response success at week 6 and end of treatment (EOT), all-causality mortality and time to death. Voriconazole exposure-response relationship was explored.

Results: Of 53 voriconazole-treated pediatric patients (31 IA; 22 IC/EC), 14 had proven/probable IA, 7 had confirmed IC and 10 had confirmed EC. Treatment-related hepatic and visual adverse events, respectively, were reported in 22.6% and 16.1% of IA patients, and 22.7% and 27.3% of IC/EC patients. All-causality mortality in IA patients was 14.3% at week 6; no deaths were attributed to voriconazole. No deaths were reported for IC/EC patients. Global response success rate was 64.3% (week 6 and EOT) in IA patients and 76.5% (EOT) in IC/EC patients. There was no association between voriconazole exposure and efficacy; however, a slight positive association between voriconazole exposure and hepatic adverse events was established.

Conclusions: Safety and efficacy outcomes in pediatric patients with IA and IC/EC were consistent with previous findings in adult patients.

Trial registration: ClinicalTrials.gov NCT00836875 NCT01092832.

Figures

FIGURE 1.

Patient disposition. aAll patients who received ≥1 voriconazole dose. bAll patients with proven/probable IA, microbiologically confirmed IC, presumed EC or microbiologically confirmed EC who received ≥1 voriconazole dose. cPatients who discontinued study treatment for any reason were not considered to have completed treatment. AE indicates adverse event; EC, esophageal candidiasis; IA, invasive aspergillosis; IC, invasive candidiasis; MITT, modified intent-to-treat.

FIGURE 2.

Global response success rates at EOT in patients with IA and IC/EC (MITT population). EC indicates esophageal candidiasis; EOT, end of treatment; IA, invasive aspergillosis; IC, invasive candidiasis; MITT, modified intent-to-treat.

FIGURE 3.

Basic goodness-of-fit plots for the final pharmacokinetic model, showing: observed concentrations versus population predicted concentrations (A); observed concentrations versus individually predicted concentrations (B); conditional weighted residuals versus individually predicted concentrations (C); conditional weighted residuals versus time (D). Open circles represent observed data; the dashed line represents the line of identity or unity; the solid line represents the local regression smooth line (loess smooth). The closer the smooth line is to the line of identity or unity, the more robust the model fit.

FIGURE 4.

Observed and model-predicted probability of treatment-related hepatic AEs versus voriconazole Cmin (A) and all-causality hepatic AEs versus voriconazole AUC0–12 (B) using multiple-panel data. “|” symbols represent observed individual data (AE present = 1, AE absent = 0); solid circles represent the observed probability of an AE at each concentration level (note: individual concentration values were rounded up to the next integral value for summary purposes). The line and the corresponding band represent the population-predicted probability and its 95% CI (computed with 1000 bootstrap). A wide 95% CI indicates low precision on the probability prediction. AE indicates adverse event; AUC0–12, area under the curve from 0 to 12 hours; CI, confidence interval; Cmin, minimum plasma concentration (trough).

FIGURE 5.

EOT global response versus voriconazole AUC0–12 and Cmin in patients with IA (A) and patients with EC (B). Horizontal center line represents the median; box represents the interquartile distance; whiskers represent ≤1.5 × interquartile range; solid circles represent the estimated individual exposure parameters. AUC0–12 indicates area under the curve from 0 to 12 hours; Cmin, minimum plasma concentration (trough); EC, esophageal candidiasis; EOT, end of treatment; IA, invasive aspergillosis.

FIGURE 6.

Comparison of estimated steady-state voriconazole AUC0–12 and Cmin by age group at matching IV and oral doses in patients with IA. Horizontal center line represents the median; box represents the interquartile distance; whiskers represent ≤1.5 × interquartile range; outliers are represented by open circles beyond whiskers. Intravenous regimen: 8 mg/kg q12 h for children (aged 2–<12 years) and young adolescents (aged 12–14 years weighing <50 kg); 4 mg/kg q12 h for all other adolescents and adults with IA. Oral regimen: 9 mg/kg (max 350 mg) q12 h for children (aged 2–<12 years) and young adolescents (aged 12–14 years weighing <50 kg); 200 mg q12 h for all other adolescents and adults with IA. Note that data from adults with IA at 300 mg oral q12 h are also included here and denoted as “Adults with IA 300”. This figure was created for easy comparison across different age groups. AUC0–12 indicates area under the curve from 0 to 12 h; Cmin, minimum plasma concentration (trough); IA, invasive aspergillosis; IV, intravenous; q12 h, every 12 h.