Safety and Efficacy of Intravenous Pentamidine in Children and Adolescents Undergoing Hematopoietic Stem Cell Transplantation

Abstract

achievement of steady state. The half life (t 1/2) of voriconazole was 5.0965.15 hours. The dose normalized (per mg) AUC (mg*hr/ml) was 0.11160.081. Voriconazole dose did not correlate with AUCo-N (r 2 5 0.028). There was a good correlation between AUCo-N and C trough (r 2 5 0.94). Population estimates of bioavailability, clearance, apparent volume of the central compartment (Vc) and apparent volume of peripheral compartment (Vp) were 46.5%, 5.76L/hr, 19.4L and 58.8L. Conclusions: The bioavailability of voriconazole was significantly lower in pediatric BMT patients than in non-transplant adult subjects. The t 1/2 at steady state tended to be lower than adult patients. Our study suggests that pediatric patients may require dosing higher than 7 mg/kg twice daily. The wide individual variability and the lack of correlation between dose and AUC support therapeutic monitoring of voriconazole and dose adjustments based on steady state blood levels.

Safe and Effective Prophylaxis with Bimonthly Intravenous Pentamidine in the Pediatric Hematopoietic Stem Cell Transplant Population

“…23 Recent groups who have profiled pediatric oncology or HCT patients on monthly IV pentamidine have reported a range of overall adverse event discontinuation from 6.6% to 10%, which is comparable with our overall discontinuation rate of 11.2%, of courses with 8% discontinuation prompted by infusion reactions. 14,19,24 Major infusion-related side effects prompting discontinuation (hypotension, anaphylaxis and hemodynamic instability) were seen in 2.7% of all patients, similar when compared with 2% of patients reported by Demasi et al 18 and 1.7% in Orgel et al 14,19 Of the 4 patients, who had major reactions (hypotension or anaphylaxis), 3 were very small patients with SCID. We believe that this may have been due to inadequate dilution of the dose, which resulted in the delivery of a small volume via rapid infusion when the line was primed.…”

“…3,7,14,[18][19][20][21][22] In recent pediatric HCT literature, adverse events prompting discontinuation of monthly IV pentamidine have been reported between 6% and 10% of patients, with major events like hypotension or anaphylaxis reported in 2%-5% of patients. 14,18,19,23 Importantly, IV pentamidine has not been associated with cytopenias or delayed engraftment. 14,19,24 However, monthly IV pentamidine prophylaxis in pediatric patients has variable efficacy in preventing PCP.…”

“…In the past decade, several studies using monthly dosing of IV pentamidine in broad cohorts of immunocompromised children reported PCP infection rates between 5% and 10%, with higher infectious breakthrough in the HCT patients (as opposed to oncology patients) particularly in the <2-year-old population. 14,[18][19][20][25][26][27] Higher breakthrough in younger patients may be related to the type of immunodeficiencies seen in children of this age or to increased drug metabolism in younger patients. 19,20 In addition, pharmacokinetic studies demonstrate a 10-to-14-day elimination half-life, suggesting that monthly dosing may be inferior to more frequent administration.…”

“…3,7,14,[18][19][20] Monthly IV pentamidine is an attractive choice because of ease of delivery and its relatively benign side-effect profiles in children. 3,7,14,[18][19][20][21][22] In recent pediatric HCT literature, adverse events prompting discontinuation of monthly IV pentamidine have been reported between 6% and 10% of patients, with major events like hypotension or anaphylaxis reported in 2%-5% of patients. 14,18,19,23 Importantly, IV pentamidine has not been associated with cytopenias or delayed engraftment.…”

“…8,[15][16][17] In pediatric populations, intravenous (IV) pentamidine is often preferred over aerosolized pentamidine because of concerns for effective aerosolized delivery, particularly in younger children, who are less likely to be compliant. 3,7,14,[18][19][20] Monthly IV pentamidine is an attractive choice because of ease of delivery and its relatively benign side-effect profiles in children. 3,7,14,[18][19][20][21][22] In recent pediatric HCT literature, adverse events prompting discontinuation of monthly IV pentamidine have been reported between 6% and 10% of patients, with major events like hypotension or anaphylaxis reported in 2%-5% of patients.…”