Assessment of the Effective Dose of Isavuconazole, Itraconazole, Posaconazole, and Voriconazole to Achieve Goal Serum Concentrations in Pediatric Patients at a Single Center

Introduction

Prompt initiation of effective triazole doses for invasive fungal infections (IFIs) is of paramount importance to optimize patient clinical outcome owing to the substantial morbidity and mortality associated with IFIs, especially in critically ill and immunocompromised pediatric patients. Thus, the standard of care for most triazole therapy generally includes therapeutic drug monitoring (TDM) to optimize efficacy and limit toxicity. TDM is particularly imperative in the pediatric population because there is substantial inter- and intra-patient variability, resulting in variable responses to antifungal agents. Pediatric patients often require dose adjustments owing to alterations in pharmacokinetics that occur as they develop from a neonate through adolescence.^1,2 Additionally, there are limited data behind current recommended doses, most agents are not fully approved for the pediatric population, and doses are often extrapolated from or compared with the adult population. Currently, there are 5 triazole antifungals used for IFI: isavuconazole, itraconazole, posaconazole, voriconazole, and fluconazole. Of these 5, in the pediatric population TDM is most routinely done for isavuconazole, itraconazole, posaconazole, and voriconazole.

Selecting the best starting dose for pediatric patients is extremely challenging and dependent on a multitude of host and drug factors such as gastrointestinal ­absorption, volume of distribution, hepatic and renal clearance, pharmacogenetics, drug formulations, and more.^1,2 Recommended starting doses of triazole antifungals for pediatric patients as described in the literature are summarized in Table 1.

Table 1.Summary of Recommended Therapeutic Azole Dose Ranges in the Literature

View Fullscreen

There are limited data in pediatrics that conclusively evaluate the relationship between recommended doses and goal serum concentrations. Thus, the primary outcome of this study was to determine the effective dose needed to reach goal serum concentrations of isavuconazole, itraconazole, posaconazole, and voriconazole in pediatric patients. The secondary aim focuses on identifying the interrelationships between indications and targeted drug concentrations for the 4 azoles. Determining the suitable dose in pediatric patients can help decrease time to attainment of therapeutic serum concentrations and avert adverse effects and toxicities.

Materials and Methods

A single center, retrospective chart review was conducted in pediatric patients from birth through 17 years of age who received isavuconazole, itraconazole, posaconazole, or voriconazole between January 1, 2011, and August 31, 2021. Patients were only included if they had an inpatient or outpatient encounter with at least 1 antifungal drug serum concentration measurement. Drug concentrations for itraconazole, posaconazole, and voriconazole are processed in-house and typically take about 24 hours for results. Drug concentrations for isavuconazole are sent to Eurofins Viracor, LLC, and results are typically available within 5 to 7 days. Patients were excluded if they did not have TDM performed, electronic medical record had incomplete information (i.e., unknown starting azole dose or date), posaconazole immediate-release oral suspension was prescribed, or there was documented refusal of research authorization. Data collected was captured in a secured REDCap (Research Electronic Data; Vanderbilt University, Nashville, TN) database.

Antifungal doses (mg/kg/day) and time (days to first goal concentration) needed to achieve goal serum concentrations of isavuconazole, itraconazole, posaconazole, and voriconazole in pediatric patients were analyzed. The impact of antifungal doses and time to goal concentrations were assessed through documented therapy initiation and acceptable serum trough concentration following the achievement of steady-state concentrations of the medication. We defined steady state as 4 weeks for isavuconazole, 14 days for itraconazole, 7 days for posaconazole, and 5 days for voriconazole. Isavuconazole concentrations were obtained prior to the conversion to maintenance dosing on day 3 (after the 6-dose load) and then again at 14 or 28 days dependent on indication for use, 10 to 14 days for itraconazole, 6 to 7 days for posaconazole, and at 5 days for voriconazole. Concentrations were considered at goal if within the following range for each antifungal: isavuconazole >1 mg/L, itraconazole >1 mg/L (via high-performance liquid chromatography, excluding hydroxy-itraconazole metabolite), posaconazole (prophylaxis) >0.7 mg/L, posaconazole (treatment) >1 mg/L, and voriconazole >1 mg/L or if there was a different concentration noted in the provider’s clinical note. Hydroxy-itraconazole is an active metabolite of itraconazole that is reported to have comparable in vitro activity.² However, recommendations are mixed as to whether the hydroxy-itraconazole component should be used in assessing efficacy; therefore, attainment of targeted range by the parent compound alone was used. Duration of antifungal therapy was calculated as the interval between the first dose given and the dose at the time of a goal concentration (or end-of-study concentration if a goal concentration was not achieved).

Interrelationship between indications and dose required for the different azoles in pediatric patients was examined. Patients were divided into 2 groups. The empiric group included patients who were receiving the antifungal for prophylaxis/prevention or empiric treatment of a fungal infection without microbiologic evidence because goal concentrations would be similar for prophylaxis and empiric treatment. Patients were included into the targeted therapy group if there was microbiologic evidence of fungal infection.

Baseline and end-of-study monitoring of liver function tests and renal function were also evaluated. End of study was defined as achievement of goal concentration for that antifungal. Liver and renal function were assessed to monitor for any potential toxicity due to drug concentrations or alterations to drug clearance that may have affected drug concentrations. Drug doses were not adjusted on the basis of specific liver or kidney function result but were used as part of full patient assessment and to assist with how therapy could be individualized. For patients who did not meet goal concentration, end of therapy was defined as when antifungal therapy was stopped or as a switch to another agent. Laboratory evaluations included alanine transaminase (ALT), aspartate transaminase, total bilirubin, alkaline phosphate, and serum creatinine. Significant changes were defined as 3 times the upper limit of normal from baseline for hepatic markers and a 50% increase from baseline for serum creatinine. These monitoring laboratory results must have been obtained within 1 week of starting azole therapy and similarly within 1 week of the defined end-of-study period.

Data were summarized by using frequencies and percentages for categorical data and medians and IQRs for continuous data. Comparisons between treatment regimens were made by using chi-square or Fisher exact tests for categorical data and Kruskal-Wallis tests for continuous data. Time-to-therapeutic concentration was assessed by using the Kaplan-Meier method and Cox proportional hazards regression. A spline plot was used to assess the functional form of the relationship between dose and likelihood of achieving a therapeutic concentration. A spline plot and a cut-point analysis were used to determine a dose cutoff where patients were more likely to achieve a therapeutic concentration. Among those who achieved a therapeutic concentration, a scatter plot and linear regression were used to assess the association between starting dose and time needed to reach therapeutic concentration for each treatment regimen. The regression models were also used to assess if there was an interaction between starting dose and indication (i.e., if there are different relationships based on medication indication). All analyses were performed with SAS version 9.4 software (SAS Institute Inc, Cary, NC).

Results

During the 10.5-year study period, 273 patients received isavuconazole, itraconazole, posaconazole, or voriconazole in the inpatient or outpatient setting. One hundred fifty-one patients were excluded, and 122 patients were included in the analysis (Figure 1).

View Figure

• Download as Powerpoint
• Download Figure

Baseline characteristics are described in Table 2. Median patient age was 13 years (IQR, 8.1–15.9) with 57% aged 12 years or older. Notably, 84% of the population received either itraconazole or voriconazole and most patients (72%) were classified as receiving targeted treatment for an identified fungal organism. Approximately half of the patients in the cohort had a diagnosis of either aspergillosis (32 patients; 26%) or histoplasmosis (32 patients; 26%).

Table 2.Baseline Characteristics

View Fullscreen

Goal serum concentration was achieved by 101 patients (83%) (Table 3). Approximately 83% of patients who reached a goal concentration received either itraconazole or voriconazole. Median time to goal concentration occurred at 20 days for isavuconazole, 34 days for itraconazole, 11 days for posaconazole, and 10 days for voriconazole. The dosage in mg/kg/dose was higher for patients younger than 12 years for all azoles. This was expected owing to this group’s having a lower weight. However, total mg/dose/day was similar for both the <12-year age group and ≥12-year group (Figure 2A and B). For patients younger than 12 years, the median doses that achieved goal concentrations were the following: 11.1 mg/kg/day (372 mg/day) for isavuconazonium sulfate, 10 mg/kg/day (300 mg/day) for itraconazole, 6.8 mg/kg/day (300 mg/day) for posaconazole, and 17.9 mg/kg/day (365 mg/day) for voriconazole. For patients 12 years or older who achieved an appropriate drug concentration, the median dose that was used to achieve the goal was as follows: 5.5 mg/kg/day (186 mg/day) for isavuconazonium sulfate, 6.9 mg/kg/day (400 mg/day) for itraconazole, 6.1 mg/kg/day (300 mg/day) for posaconazole, and 8.5 mg/kg/day (600 mg) for voriconazole. Patients who received higher doses of voriconazole were more likely to reach goal concentration. This is further described in 3 dosing subgroups where differences in total daily dose or mg/kg/day dosing were noted (Figure 2C and D; Table 4).

View Figure

• Download as Powerpoint
• Download Figure

Table 3.Patients Who Reached Goal Serum Azole Concentration (All Measures Are at Time of Goal Concentration)

View Fullscreen

Table 4.Dosing Subgroups*

View Fullscreen

Table 5 describes the association between baseline characteristics and chances of obtaining goal concentrations. Posaconazole (hazard ratio [HR], 2.67; 95% CI, 1.41–5.05; p = 0.003) and voriconazole (HR, 2.98; 95% CI, 1.89–4.69; p < 0.001) were more likely to reach goal concentrations than itraconazole. There was no significant difference in reaching a goal concentration between participants who were in the empiric group and the targeted treatment group (HR, 1.06; 95% CI, 0.68–1.65; p = 0.80). There was no statistically significant difference in liver function tests or serum creatinine from baseline.

Table 5.Associations Between Achieving a Goal Level and Baseline Characteristics

View Fullscreen

Discussion

To our knowledge, this study is the first to evaluate the dose and time to therapeutic serum concentrations of isavuconazole, itraconazole, posaconazole, and voriconazole and adds to the growing body of literature for azole use in pediatric patients. Understanding the optimal doses to obtain appropriate serum concentrations of these antifungals is increasingly important owing to the major morbidity and mortality consequences that difficult-to-treat IFIs can have. Noting the differences in azole half-life, our study found that the median number of days to reach goal steady-state serum concentrations varied among the azoles, mainly owing to the different frequency at which a concentration is obtained. Additionally, most azoles reached goal concentrations with the second drug assessment after at least 1 dose adjustment. With this observation, initiating azole antifungal therapy at a higher starting dose would lead to achieving goal concentrations sooner. It is important to minimize the time to reach goal serum drug concentrations to hopefully limit antifungal resistance and clinical failures/breakthrough infection associated with extended periods of suboptimal antifungal concentrations. Additional factors that could affect treatment outcomes include route of administration, drug formulations, duration of therapy, renal or hepatic abnormalities, and drug-drug interactions. Some of these factors will be further touched on for each antifungal in the following paragraphs. Renal and hepatic laboratory values are described in Table 2 and Table 3. There were no statistically significant changes in renal or hepatic function tests from baseline.

Limitations

This study is not without limitations. The retrospective design prevented the ability to account for any confounders such as patient adherence and appropriate timing and frequency of serum azole concentrations. A new electronic medical record system was implemented in May 2018 at our institution, thus making the data collection prior to that period challenging. Additionally, there was no dedicated pediatric antimicrobial stewardship/infectious diseases pharmacist at our institution prior to 2019. The lack of pharmacist input did affect the frequency and possibly the accuracy of TDM in the beginning of our study cohort. However, TDM concentrations have become standardized in the past few years with a pediatric infectious diseases pharmacist integrated into the multidisciplinary team. Additionally, the study only assessed the first serum concentration within goal range and did not account for dosage form variations and serum concentration fluctuations over the course of the patient’s therapy (i.e., auto-induction seen with voriconazole). Therefore, how a patient’s dose may change over time was not evaluated. We also were not able to assess underlying conditions and comorbidities that may have affected absorption and overall disposition. Another limitation was the omission of cytochrome P4502C19 (CYP2C19) pharmacogenomic testing assessment and the impact of inflammation on voriconazole concentrations. CYP2C19 testing is available at our institution but not always done as standard of practice. Finally, posaconazole delayed-release oral suspension was not assessed in this study because it was not available during the study time frame.

Conclusions

In summary, higher starting daily doses are generally needed to reach goal concentrations for all azoles evaluated. Dose recommendations based on our findings are summarized in Table 6. These doses are meant to serve as first-dose guidance and are within the range described in the current literature. Individualized dosing should be based on indication and other patient characteristics combined with serum drug concentration monitoring. Higher-than-suggested doses may still be warranted based on the clinical situation especially if the patient is at relatively low risk for toxicity with a more aggressive dosing approach upfront.

Table 6.Recommended Azole Starting Doses

View Fullscreen