Pharmacokinetics and Safety of Intravenous Voriconazole in Children after Single- or Multiple-Dose Administration

Abstract

We conducted a multicenter study of the safety, tolerability, and plasma pharmacokinetics of the parenteral formulation of voriconazole in immunocompromised pediatric patients (2 to 11 years old). Single doses of 3 or 4 mg/kg of body weight were administered to six and five children, respectively. In the multiple-dose study, 28 patients received loading doses of 6 mg/kg every 12 h on day 1, followed by 3 mg/kg every 12 h on day 2 to day 4 and 4 mg/kg every 12 h on day 4 to day 8. Standard population pharmacokinetic approaches and generalized additive modeling were used to construct the structural pharmacokinetic and covariate models used in this analysis. In contrast to that in adult healthy volunteers, elimination of voriconazole was linear in children following doses of 3 and 4 mg/kg every 12 h. Body weight was more influential than age in accounting for the observed variability in voriconazole pharmacokinetics. Elimination capacity correlated with the CYP2C19 genotype. Exposures were similar at 4 mg/kg every 12 h in children (median area under the concentration-time curve (AUC), 14,227 ng ⅐ h/ml) and 3 mg/kg in adults (median AUC, 13,855 ng ⅐ h/ml). Visual disturbances occurred in 5 (12.8%) of the 39 patients and were the only drug-related adverse events that occurred more than once. No withdrawals from the study were related to voriconazole. We conclude that pediatric patients have a higher capacity for elimination of voriconazole per kilogram of body weight than do adult healthy volunteers and that dosages of 4 mg/kg may be required in children to achieve exposures consistent with those in adults following dosages of 3 mg/kg.

Severe primary cutaneous aspergillosis refractory to amphotericin B and the successful treatment with systemic voriconazole in two premature infants with extremely low birth weight

“…5 A large comparative trial in immunocompromised adult patients with invasive aspergillosis established the superiority of voriconazole over amphotericin B in terms of clinical response and survival (hazard ratio for mortality 0.59). 7 Walsh et al 8,9 first reported on the use of voriconazole in immunocompromised pediatric patients and achieved a respectable success rate with a very low incidence of side effects.…”

Voriconazole plasma levels in children are highly variable

“…In contrast, the clearance in children remains linear over a comparable dose range [4,5]. In addition, the oral bio-availability of voriconazole is two-fold lower in children (45%) than in adults (96%) [5].…”

“…It has been shown in several pharmacokinetic studies that voriconazole is cleared much more rapidly in children than in adults [4,5]. Pharmacokinetic profiles are different in these two populations [4,5].…”

“…To our knowledge, until recently, only 2 studies were available on voriconazole pharmacokinetics in children under 12 years of age [4,5].…”

Farmacología de los azoles

“…Voriconazol muestra un perfil de eliminación dependiente de la edad, caracterizado por un aumento del aclaramiento y reducción de la semivida de eliminación de origen no aclarado, pero relacionado probablemente con diferencias en la actividad de las CYP450, y que exige la administración de dosis superiores a las utilizadas habitualmente en adultos [33].…”