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

• Published in: PloS one Vol. 14; no. 3; p. e0212837
• Main Authors: Arrieta, Antonio C., Sung, Lillian, Bradley, John S., Zwaan, C. Michel, Gates, Davis, Waskin, Hetty, Carmelitano, Patricia, Groll, Andreas H., Lehrnbecher, Thomas, Mangin, Eric, Joshi, Amita, Kartsonis, Nicholas A., Walsh, Thomas J., Paschke, Amanda
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 26.03.2019; Public Library of Science (PLoS)
• Subjects: Administration, Oral; Adolescent; Adults; Age; Age Factors; Antifungal agents; Antifungal Agents - administration & dosage; Antifungal Agents - adverse effects; Antifungal Agents - pharmacokinetics; Antineoplastic Agents; Area Under Curve; Biology and Life Sciences; Bone marrow; Cancer therapies; Chemotherapy; Child; Child, Preschool; Children; Dosage; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug dosages; Exposure; Female; Formulations; Fungal infections; Fungicides; Health aspects; Hospitals; Humans; Immunocompromised Host; Infant; Infection; Infectious diseases; Invasive Fungal Infections - drug therapy; Invasive Fungal Infections - immunology; Invasive Fungal Infections - prevention & control; Laboratories; Leukemia; Male; Medicine and Health Sciences; Mycoses; Neoplasms - drug therapy; Neutropenia; Neutropenia - chemically induced; Neutropenia - complications; Neutropenia - immunology; Oncology; Oral drugs; Pediatrics; People and Places; Pharmacokinetics; Pharmacology; Population; Posaconazole; Prophylaxis; Prospective Studies; Research and Analysis Methods; Safety; Steady state; Transplants & implants; Triazoles; Triazoles - administration & dosage; Triazoles - adverse effects; Triazoles - pharmacokinetics; Canada; Netherlands; United States > US; Germany
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0212837

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.