Research Article: A non-randomized trial to assess the safety, tolerability, and pharmacokinetics of posaconazole oral suspension in immunocompromised children with neutropenia

Date Published: March 26, 2019

Publisher: Public Library of Science

Author(s): Antonio C. Arrieta, Lillian Sung, John S. Bradley, C. Michel Zwaan, Davis Gates, Hetty Waskin, Patricia Carmelitano, Andreas H. Groll, Thomas Lehrnbecher, Eric Mangin, Amita Joshi, Nicholas A. Kartsonis, Thomas J. Walsh, Amanda Paschke, Doan TM Ngo.

http://doi.org/10.1371/journal.pone.0212837

Abstract

Posaconazole (POS) is a potent triazole antifungal agent approved in adults for treatment and prophylaxis of invasive fungal infections (IFIs). The objectives of this study were to evaluate the pharmacokinetics (PK), safety, and tolerability of POS oral suspension in pediatric subjects with neutropenia.

This was a prospective, multicenter, sequential dose-escalation study. Enrolled subjects were divided into 3 age groups: AG1, 7 to <18 years; AG2, 2 to <7 years; and AG3, 3 months to <2 years. AG1 and AG2 were divided into 3 dosage cohorts: DC1, 12 mg/kg/day divided twice daily (BID); DC2, 18 mg/kg/day BID; and DC3, 18 mg/kg/day divided thrice daily (TID). AG3 was also divided into DC1 and DC2; however, no subjects were enrolled in DC2. Subjects received 7–28 days of POS oral suspension. PK samples were collected at predefined time points. The POS PK target was predefined as ~90% of subjects with Cavg (AUC /dosing interval) between 500 and 2500 ng/mL, with an anticipated mean steady state Cavg exposure of ~1200 ng/mL. The percentage of subjects meeting the PK target was <90% across all age groups and dosage cohorts (range: 31% to 80%). The percentage of subjects that achieved the Cavg target of 500 to 2500 ng/mL on Day 7 ranged from 31% to 80%, with the lowest proportion in subjects 2 to <7 years receiving 12 mg/kg/day BID (AG2/DC1) and the highest proportion in subjects 7 to <18 years receiving 18 mg/kg/day TID (AG1/DC3). At all three dose levels (12 mg/kg/day BID, 18 mg/kg/day BID and 18 mg/kg/day TID), subjects in AG1 (7 to <18 years old) had higher mean PK exposures at steady state than those in AG2. High variability in exposures was observed in all groups. POS oral suspension was generally well tolerated and most of the reported adverse events were related to the subjects’ underlying diseases. The POS PK target of 90% of subjects with Cavg between 500 and 2500 ng/mL was not achieved in any of the age groups across the different dosage cohorts. New formulations of the molecule with a greater potential to achieve the established PK target are currently under investigation. ClinicalTrials.gov identifier: NCT01716234

Partial Text

Pediatric subjects who receive dose-intensive chemotherapy for cancer are at an increased risk of invasive fungal infections (IFIs). The pediatric population at high risk for developing IFIs includes, but is not limited to, allogeneic hematopoietic stem cell transplant (HSCT) recipients, patients with acute myeloid leukemia (AML), relapsed acute lymphoblastic leukemia (ALL), or severe aplastic anemia, and patients receiving immunosuppressant or high-dose corticosteroids for severe graft-versus-host disease (GVHD) or other conditions [1–6]. IFIs are responsible for considerable morbidity, mortality, and healthcare utilization and may prevent or delay the delivery of appropriate chemotherapy [7, 8]. Additionally, the incidence of IFIs in the pediatric population appears to have increased over the past few decades, primarily because of the prolonged survival of pediatric patients with primary or secondary immune deficiencies [9–11]. Prophylaxis for IFIs is indicated in high-risk pediatric patients, and recommended agents include fluconazole, liposomal amphotericin, and micafungin; however, more clinical data supporting use of newer antifungal agents in this population are needed, particularly with regard to appropriate pediatric dosing [12].

The PK and safety of the POS oral suspension in the pediatric population was characterized in this study. POS oral suspension was administered at dosages of 12 mg/kg/day (DC1) in two divided doses, and 18 mg/kg/day in two (DC2) and three divided doses (DC3). Despite assessments at different dosages and varying dose intervals, the POS oral suspension failed to achieve the PK target for the study (i.e., >90% of pediatric subjects with a steady state Cavg of 500 ng/ml– 2500 ng/ml). Nonetheless, some individual subjects did attain the target levels of 500 to 2500 ng/mL on Day 7 with the lowest proportion in AG2(2y to <7 y) /DC1(12mg/kg/d, BID) subjects and the highest proportion in subjects being AG1(7y to <18 y) /DC3(18mg/kg/d, TID). At all three dose levels, subjects in AG1(7y to <18y) had higher mean PK exposures at steady state than those in AG2(2y to < 7y).   Source: http://doi.org/10.1371/journal.pone.0212837

 

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