Five‐year‐survey of invasive aspergillosis in a paediatric cancer centre. Epidemiology, management and long‐term survival

308

234

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.

mentioning

confidence: 99%

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

Walsh

Karlsson

Driscoll

et al. 2004

308

234

“…However, invasive fungal infections remain an important cause of infection-related mortality and morbidity in pediatric patients (1,6,9,14). Recent advances in the early diagnosis, prevention, and treatment of fungal infections offer hope to these patients (2,10,13).…”

mentioning

confidence: 99%

Safety, Tolerability, and Pharmacokinetics of Micafungin (FK463) in Febrile Neutropenic Pediatric Patients

Seibel

Schwartz

Arrieta

et al. 2005

221

145

Micafungin (FK463) is a new parenteral echinocandin. A multicenter, phase I, open-label, sequential-group dose escalation study was conducted to assess the safety, tolerability, and pharmacokinetics of micafungin in neutropenic pediatric patients. A total of 77 patients stratified by age (2 to 12 and 13 to 17 years) received micafungin. Therapy was initiated at 0.5 mg/kg per day and escalated to higher dose levels of 1.0, 1.5, 2.0, 3.0, and 4.0 mg/kg per day. Micafungin was administered within 24 h of initiating broad-spectrum antibacterial antibiotics for the new onset of fever and neutropenia. The most common overall adverse events in the study population were diarrhea (19.5%), epistaxis (18.2%), abdominal pain (16.9%), and headache (16.9%). Nine patients (12%) experienced adverse events considered by the investigator to be possibly related to the study drug. The most common related events were diarrhea, vomiting, and headache, all occurring in two patients each. There was no evidence of a dose-limiting toxicity as defined within the prespecified criteria of this clinical protocol. There was one death during the study due to septic shock. The pharmacokinetic profiles for micafungin over the 0.5-to 4.0-mg/kg dose range demonstrated dose linearity. Clearance, volume of distribution, and half-life remained relatively constant over the dose range and did not change with repeated administration. The overall plasma pharmacokinetic profile was similar to that observed in adults. However, there was an inverse relation between age and clearance. For patients 2 to 8 years old, clearance was approximately 1.35 times that of patients >9 years of age. In summary, micafungin over a dosage range between 0.5 and 4.0 mg/kg/day in 77 febrile neutropenic pediatric patients displayed linear pharmacokinetics and increased clearance as a function of decreasing age.Advances in cytotoxic chemotherapy, transplantation procedures, and supportive care have increased survival in children with leukemia and other neoplasms (4,11,28). However, invasive fungal infections remain an important cause of infection-related mortality and morbidity in pediatric patients (1,6,9,14). Recent advances in the early diagnosis, prevention, and treatment of fungal infections offer hope to these patients (2, 10, 13). Among the newer classes of antifungal compounds are the echinocandins, which have offered broad-spectrum activity and a favorable safety profile in adult patients (3).Currently, the two most common invasive fungal infections in neutropenic adult and pediatric patients are caused by Candida spp. and Aspergillus spp. Micafungin (FK463; Fujisawa Healthcare, Inc., Deerfield, IL) is an intravenous antifungal compound of the echinocandin class. Micafungin acts by inhibiting the production of 1,3-␤-D-glucan, a key component in fungal cell wall synthesis (12). A semisynthetic lipopeptide, micafungin possesses in vitro and in vivo activity against a broad spectrum of Candida and Aspergillus species, including activity against azole-resistant Candida (8,1...

“…Invasive pulmonary aspergillosis is an important cause of morbidity and mortality in patients receiving cytotoxic chemotherapy for leukemia, bone marrow transplantation, and aplastic anemia (3,12,15,28,44,45). Amphotericin B (AMB) is the most widely used drug for treating invasive pulmonary aspergillosis; however, its use is limited by dose-dependent nephrotoxicity (20,53).…”

mentioning

confidence: 99%

Antifungal Efficacy of Caspofungin (MK-0991) in Experimental Pulmonary Aspergillosis in Persistently Neutropenic Rabbits: Pharmacokinetics, Drug Disposition, and Relationship to Galactomannan Antigenemia

Petraitienė

Petraitis

Groll

et al. 2002

175

124

The antifungal efficacy, pharmacokinetics, and safety of caspofungin (CAS) were investigated in the treatment and prophylaxis of invasive pulmonary aspergillosis due to Aspergillus fumigatus in persistently neutropenic rabbits. Antifungal therapy consisted of 1, 3, or 6 mg of CAS/kg of body weight/day (CAS1, CAS3, and CAS6, respectively) or 1 mg of deoxycholate amphotericin B (AMB)/kg/day intravenously for 12 days starting 24 h after endotracheal inoculation. Prophylaxis (CAS1) was initiated 4 days before endotracheal inoculation. Rabbits treated with CAS had significant improvement in survival and reduction in organism-mediated pulmonary injury (OMPI) measured by pulmonary infarct score and total lung weight (P < 0.01). However, animals treated with CAS demonstrated a paradoxical trend toward increased residual fungal burden (log CFU per gram) and increased serum galactomannan antigen index (GMI) despite improved survival. Rabbits receiving prophylactic CAS1 also showed significant improvement in survival and reduction in OMPI (P < 0.01), but there was no effect on residual fungal burden. In vitro tetrazolium salt hyphal damage assays and histologic studies demonstrated that CAS had concentration-and dose-dependent effects on hyphal structural integrity. In parallel with a decline in GMI, AMB significantly reduced the pulmonary tissue burden of A. fumigatus (P < 0.01). The CAS1, CAS3, and CAS6 dose regimens demonstrated dose-proportional exposure and maintained drug levels in plasma above the MIC for the entire 24-h dosing interval at doses that were >3 mg/kg/day. As serial galactomannan antigen levels may be used for therapeutic monitoring, one should be aware that profoundly neutropenic patients receiving echinocandins for aspergillosis might have persistent galactomannan antigenemia despite clinical improvement. CAS improved survival, reduced pulmonary injury, and caused dose-dependent hyphal damage but with no reduction in residual fungal burden or galactomannan antigenemia in persistently neutropenic rabbits with invasive pulmonary aspergillosis.