Voriconazole Dosing in Children Younger Than 3 Years Undergoing Cancer Chemotherapy or Hematopoietic Stem Cell Transplantation

Abstract

Voriconazole therapeutic drug monitoring improves the drug’s efficacy and safety in patients with invasive fungal infections (IFIs). Previously published reports of studies in adult patients have suggested aiming for a plasma trough drug concentration between 1 and 5.5 mg/L for efficacy and limiting toxicity [1]. Keeping patients within this target range, however, can be difficult because of significant intraindividual variability. In a study of adult hematopoietic stem cell transplant (HSCT) recipients, only 67% maintained a trough concentration of ≥1 mg/L on subsequent measurement [2].

Data on optimal voriconazole dosing and pharmacokinetics (PK) studies have been limited in pediatrics; only isolated case reports for children younger than 2 years are available. The objective of this study was to determine the proportion of children younger than 3 years who achieved the target trough concentration of ≥1 mg/L and to assess for variability in trough levels and dosing.

METHODS

This study was reviewed and approved by the Institutional Review Board at Memorial Sloan Kettering Cancer Center (MSKCC) in New York City. It was a retrospective review of 34 pediatric (<3-year-old) patients with cancer who had received voriconazole for prophylaxis, empiric antifungal therapy for persistent fever and neutropenia (F&N), or treatment of IFI at MSKCC between January 1, 2002, and February 12, 2015. We included patients for whom at least 1 steady-state trough measurement was made after they received ≥5 days of voriconazole and for whom repeat trough levels were measured at least 3 days after a change in dose or formulation. Trough levels were measured immediately before giving the next dose. All the patients received their doses at 12-hour intervals; loading doses were not given. Voriconazole levels were measured via liquid chromatography-tandem mass spectrometry (analytical range, 0.2–10 mg/L) by a reference laboratory until May 2014, at which time the use of an in-house assay was implemented [3].

Prophylaxis was initiated for high-risk patients with acute myelogenous leukemia or myelodysplastic syndrome who were receiving induction chemotherapy or undergoing allogeneic HSCT. Empiric antifungal therapy was administered to patients with ≥7 days of persisting F&N [4]. Patients receiving voriconazole for treatment had proven or probable infection on the basis of standard criteria [5].

The proportion of patients with an initial serum trough drug level of ≥1 mg/L was determined. Initial trough concentrations were also examined to assess interindividual variability, and differences between 2 separate levels measured in the same patient were used to assess intraindividual variability. Treatment failure was defined as (1) breakthrough proven or probable IFI while on prophylaxis or empiric F&N therapy or (2) a lack of improvement or progression of IFI despite voriconazole treatment. Toxicities, liver function test (LFT) results, and corrected QT interval (QTc) prolongation were evaluated on the basis of Common Terminology Criteria for Adverse Events (CTCAE) [6]. We included patients with grade 2 or higher LFT abnormalities and grade 1 or higher QTc prolongation. For each patient, the number of concurrent medications that have the potential to alter serum voriconazole concentrations or to increase the risk of QTc prolongation was also recorded.

Patient characteristics were summarized with medians and ranges for continuous covariates and frequency and percentage for categorical covariates. Correlation was evaluated using Spearman correlation. The association between a dose of ≥8 mg/kg and a trough concentration of ≥1 mg/L was tested using the Fisher’s exact test. All statistical analyses were performed in R 3.1.1 (R Foundation, Vienna, Austria).

RESULTS

Patient characteristics, underlying diagnosis, and indication for voriconazole are shown in Table 1. Of the 34 patients, 23 (68%) were <2 years old. For initial dosing, 11 patients received ≥8 mg/kg every 12 hours (range, 8–20 mg/kg), and 23 received <8 mg/kg every 12 hours (range, 3.3–7 mg/kg). An initial trough measurement of ≥1 mg/L did not correlate strongly with the dose (Spearman coefficient, 0.41). A majority (23 [68%]) of the patients had a low initial serum concentration (<1 mg/L), whereas 9 (26%) achieved a trough level between 1 and 5.5 mg/L, and 2 (6%) patients had a trough level of >5.5 mg/L. Among the 23 patients younger than 2 years, only 4 (17%) had a trough level between 1 and 5.5 mg/L, whereas the remainder (83%) had a trough level of <1 mg/L. Children who had a trough level of <1 mg/L were younger (P = .012) and weighed less (P = .036) than those with a trough level of ≥1 mg/L (Table 1). There were no significant differences between the prophylaxis and treatment groups with respect to median dose (6 vs 7.2 mg/kg, respectively; P = .19) or median trough level (0.5 vs 0.4 mg/L, respectively; P = .84).

The initial median trough level among patients who were receiving intravenous (iv) voriconazole was 0.5 mg/L (range, <0.1–5.1) compared to the median trough level of 0.3 mg/L (range, <0.1–19) among patients who were receiving oral (po) voriconazole (P = .634). The iv and po groups had frequently low initial concentrations (10 [67%] of 15 vs 13 [68%] of 19, respectively). We found large variability in trough concentrations across the patients (coefficient of variation, 243%). This result was driven mostly by 3 patients with high concentrations (5, 15, and 19 mg/L). The remaining patients had a concentration between <0.1 and 1.7 mg/L. Dosing varied from 3.3 to 19.6 mg/kg per dose. Twenty-two (65%) patients had 2 trough measurements available, and the second level occurred a median of 13 days (range, 3–48 days) after the first measurement. We found poor correlation between the 2 trough measurements (–0.06; P = .807). Of the 22 patients, 15 had dose changes and 7 did not; the correlation between the first and second trough levels was lower in patients whose dose had changed (Spearman coefficient, 0.49 versus 0.08).. Nine (26%) patients were changed to alternative antifungal therapy because of their low serum voriconazole concentrations. Of these patients, 1 with probable aspergillosis was changed to liposomal amphotericin B after 18 days because of low levels and persistent fever; the remaining 8 patients were in the prophylactic group. There were no documented breakthrough IFIs, and 3 of the 4 patients in the treatment group completed therapy.

Two patients developed an adverse drug reaction attributable to voriconazole. One patient had grade 3 LFT abnormalities that resolved while continuing voriconazole therapy at reduced doses. A second patient had a mild photosensitivity reaction that resolved after stopping the drug. Although 19 patients were receiving concomitant QTc-prolonging agents, only 1 had grade 1 QTc prolongation at day 14, but there was no baseline or follow-up electrocardiogram assessment. Six (18%) patients received concurrent medications that can increase voriconazole concentrations; none of them had an elevated trough level, and only 2 patients had a trough level of 1 mg/L and 4 patients had a low trough level (<1 mg/L). None of the patients received medications that can lower voriconazole concentrations.

DISCUSSION

Broad-spectrum antifungal agents are increasingly used in immunocompromised children with hematologic malignancy or immunodeficiency and in HSCT recipients. Triazoles such as voriconazole are available both intravenously and orally and have a favorable safety profile. Recent studies that examined the dosing and PK of voriconazole for children aged 2 to 12 years helped to define iv and po voriconazole doses to provide exposures equivalent to those for adults [7, 8]. A population PK analysis and modeling found that pediatric patients needed higher doses than adults to achieve comparable voriconazole exposure and had greater variability in exposure, especially in younger children [8]. The authors recommended that children receive an iv loading dose of 9 mg/kg and maintenance doses of 8 mg/kg or a po dose of 9 mg/kg to achieve exposure similar to that in adults receiving a 6 mg/kg loading dose and 4 mg/kg maintenance doses [8].

Our study reports on children younger than 3 years, and the majority were younger than 2 years. Because PK factors such as drug absorption, distribution, metabolism, and elimination vary depending on the age of young children, dosing and exposures to voriconazole might be different [9]. Only 9 (26%) of the children in our study achieved a trough level between 1 and 5.5 mg/L with initial dosing. Children of lower weight and age were more likely to have a trough level below 1 mg/L. The large variability in dosing (3.3–19.6 mg/kg every 12 hours) reflects limited pediatric population PK studies and pediatric dose variation over the 13-year period under review. The probability of attaining a trough level of ≥1 mg/L was 46% in patients with doses of ≥8 mg/kg (approaching doses recently suggested for children aged 2–12 years) compared to 26% in patients with doses of <8 mg/kg, but this difference did not reach statistical significance (P = .434). Voriconazole concentrations can be influenced by several PK variables, such as age, weight, absorption of po voriconazole, mucositis, genetic differences in CYP2C19 metabolism, and drug–drug interactions, all of which lead to high variability between individuals (interpatient) and within the same individual (intrapatient). This variability in serum voriconazole levels in adults has been well reported [2, 10]. Variability in the initial trough levels of 243% and lack of correlation (–0.06; P = .807) between levels 1 and 2 for a given patient suggest the same finding in our study, although they also could be results of variations in dosing.

Results of studies of children younger than 2 years are not available currently; more information on the PK of voriconazole in this group is needed. A high correlation between voriconazole exposure and trough levels was found in adults and older children, which makes voriconazole therapeutic drug monitoring useful [1, 8]. However, it is not yet clear if the trough level is a good predictor of exposure and what the target range should be in younger children.

Note

Financial support. This work was funded in part through the National Institutes of Health/National Cancer Institute Cancer Center Support Grant P30 CA008748.

Potential conflicts of interest. All authors: No reported conflicts.All authors have submitted the ICMJE Form for Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

References