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Published on: November 8, 2015
Pharmacokinetics, safety, and tolerability of voriconazole in immunocompromised children
Thomas J Walsh1, Timothy Driscoll, Peter A Milligan
1Pediatric Oncology Branch, National Cancer Institute, Bethesda, Maryland, USA. thw2003@med.cornell.edu
Insights
Higher intravenous voriconazole doses (8 mg/kg) in children achieve therapeutic plasma exposures similar to adult doses. This study evaluated higher voriconazole dosages in pediatric patients to optimize treatment for invasive fungal infections.
Area of Science:
- Pharmacology
- Pediatric Medicine
- Infectious Diseases
Background:
- Voriconazole intravenous (i.v.) dosing of 4 mg/kg in children results in lower plasma exposure (area under the concentration-time curve [AUC]) compared to adults.
- Pediatric voriconazole exposure cannot be accurately predicted using adult dosage guidelines due to pharmacokinetic differences.
- Higher voriconazole doses are needed to achieve therapeutic drug levels in pediatric patients.
Purpose of the Study:
- To evaluate the pharmacokinetics and tolerability of higher i.v.-to-oral voriconazole dosages in immunocompromised children aged 2 to <12 years.
- To determine appropriate voriconazole dosing for pediatric patients to achieve therapeutic drug exposure.
- To assess the safety and efficacy of escalated voriconazole regimens in children.
Main Methods:
- Two dosage cohorts of immunocompromised children (2 to <12 years) received escalating i.v. and oral voriconazole regimens.
- Cohort 1: 4 mg/kg i.v. q12h, then 6 mg/kg i.v. q12h, then 4 mg/kg orally (p.o.) q12h.
- Cohort 2: 6 mg/kg i.v. q12h, then 8 mg/kg i.v. q12h, then 6 mg/kg p.o. q12h.
- Pharmacokinetic parameters, including AUC over the dosing interval (AUCτ), were measured.
- Oral formulation bioavailability was assessed.
- Tolerability and adverse events were monitored.
Main Results:
- Mean AUCτ values for 4 mg/kg and 6 mg/kg i.v. in cohort 1 were 11,827 and 22,914 ng.h/ml, respectively.
- Mean AUCτ values for 6 mg/kg and 8 mg/kg i.v. in cohort 2 were 17,249 and 29,776 ng.h/ml, respectively.
- High interpatient variability in voriconazole exposure was observed.
- Oral voriconazole bioavailability in children was approximately 65%.
- Safety profiles were similar across both cohorts and age groups.
- Increased gamma glutamyl transpeptidase levels were the most common adverse event, with no correlation to voriconazole exposure.
Conclusions:
- Voriconazole was well-tolerated in children at higher dosages, irrespective of age.
- The mean plasma AUCτ for 8 mg/kg i.v. in children approximated the exposure seen with 4 mg/kg i.v. in adults.
- An 8 mg/kg i.v. dose is a rationally selected starting point for voriconazole therapy in the pediatric population.
Abstract:
The pharmacokinetics of voriconazole in children receiving 4 mg/kg intravenously (i.v.) demonstrate substantially lower plasma exposures (as defined by area under the concentration-time curve [AUC]) than those in adults receiving the same therapeutic dosage. These differences in pharmacokinetics between children and adults limit accurate prediction of pediatric voriconazole exposure based on adult dosages. We therefore studied the pharmacokinetics and tolerability of higher dosages of an i.v.-to-oral regimen of voriconazole in immunocompromised children aged 2 to <12 years in two dosage cohorts for the prevention of invasive fungal infections. The first cohort received 4 mg/kg i.v. every 12 h (q12h), then 6 mg/kg i.v. q12h, and then 4 mg/kg orally (p.o.) q12h; the second received 6 mg/kg i.v. q12h, then 8 mg/kg i.v. q12h, and then 6 mg/kg p.o. q12h. The mean values for the AUC over the dosing interval (AUCτ) for 4 mg/kg and 6 mg/kg i.v. in cohort 1 were 11,827 and 22,914 ng.h/ml, respectively, whereas the mean AUCτ values for 6 mg/kg and 8 mg/kg i.v. in cohort 2 were 17,249 and 29,776 ng.h/ml, respectively. High interpatient variability was observed. The bioavailability of the oral formulation in children was approximately 65%. The safety profiles were similar in the two cohorts and age groups. The most common treatment-related adverse event was increased gamma glutamyl transpeptidase levels. There was no correlation between adverse events and voriconazole exposure. In summary, voriconazole was tolerated to a similar degree regardless of dosage and age; the mean plasma AUCτ for 8 mg/kg i.v. in children approached that for 4 mg/kg i.v. in adults, thus representing a rationally selected dosage for the pediatric population.
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