Pharmacokinetics,Safety, and Tolerability of Voriconazole in Immunocompromised Children |
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Authors: | Thomas J. Walsh Timothy Driscoll Peter A. Milligan Nolan D. Wood Haran Schlamm Andreas H. Groll Hasan Jafri Antonio C. Arrieta Nigel J. Klein Irja Lutsar |
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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.Invasive fungal infections cause severe morbidity and mortality in immunocompromised children, particularly those with hematological malignancies and those undergoing hematopoietic stem cell transplantation (HSCT) (3, 8, 11, 19, 21, 27, 28). Voriconazole is a broad-spectrum antifungal triazole with in vitro and in vivo activity against yeasts and filamentous fungi (2, 5). Voriconazole is approved for adults for primary treatment of invasive aspergillosis, esophageal candidiasis, and candidemia in nonneutropenic patients. It is also approved for the treatment of serious, refractory infections caused by Scedosporium and Fusarium species (16, 25). Voriconazole is more effective than deoxycholate amphotericin B in treatment of invasive aspergillosis in adults, most of whom suffered from invasive pulmonary aspergillosis (9). In addition, voriconazole has been used successfully to treat aspergillosis of the central nervous system and bone (14, 20).Several case series and single case reports have described the safety and efficacy of voriconazole in pediatric oncology patients and other immunocompromised children with invasive mycoses (10, 24, 26). Voriconazole also has been used to treat Aspergillus airway disease in pediatric patients with cystic fibrosis (10). However, considerably less is known about the pharmacokinetics of this antifungal agent in children than about those in adults.Current studies indicate that there are major differences between the pharmacokinetics of voriconazole in children and those in adults. The first systematic study of the safety, tolerability, and pharmacokinetics of voriconazole in pediatric patients demonstrated linear plasma pharmacokinetics in patients receiving intravenous (i.v.) voriconazole at dosages of 3 mg/kg every 12 h (q12h) or 4 mg/kg q12h (24). By comparison, voriconazole in adults displays nonlinear Michaelis-Menten plasma pharmacokinetics following similar dosages (17, 18). These differences in pharmacokinetics between children and adults limit accurate prediction of pediatric voriconazole exposure (as defined by area under the concentration-time curve [AUC]) based on adult dosages. Indeed, pharmacokinetic modeling studies demonstrated that the AUC was approximately 3-fold lower in children receiving 4 mg/kg of voriconazole q12h than in adults receiving the same dosage.Therefore, in order to approximate the plasma exposure achieved in adults, we studied the safety, tolerability, and plasma pharmacokinetics of voriconazole in pediatric patients receiving dosages of 4, 6, and 8 mg/kg i.v. q12h. We also examined the plasma pharmacokinetics of the oral suspension of voriconazole at 4 and 6 mg/kg q12h. |
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