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

Abstract

Background: 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.

Methods: 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.

Results: 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.

Conclusion: 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.

Trial registration: ClinicalTrials.gov identifier: NCT01716234.

Conflict of interest statement

The study was sponsored and funded by Merck & Co., Inc., Kenilworth, NJ, USA; the company manufactures POSACONAZOLE under the name NOXAFIL®. The authors have the following competing interests to disclose: AA and JSB received grant funds from Merck & Co., Inc., Kenilworth, NJ, USA- to conduct the study; LS has nothing to disclose; TL reports grants and from Gilead Sciences and was an Advisory Board member/Speaker at Merck, Astellas, and Basiela; AG reports consultant fee and honorarium from Merck; CMZ reports funds for the trial reimbursement; TJW received consultant fees from Allergan, Astellas, ContraFect, Drais, iCo, Medicines Company, Merck, Novartis, Pfizer, Methylgene, SigmaTau and research grants from Weill Cornell Medicine, Allergan, Astellas, Merck, Novartis, Pfizer and Scynexis. PC, DG, AJ, NK, EM, AP, and HW are employees of Merck & Co., Inc., Kenilworth, NJ, USA. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Figures

Fig 1. Study design.

* Initial screening phase lasted up to 7 days; vital signs, medical history, and blood draws for hematology and serum chemistry assessments were taken.# Minimum duration of treatment was 7 days and continued until resolution of neutropenia or initiation of SOC treatment for IFI, up to a maximum of 28 days. Note: Blood draws for full PK assessments were obtained on Day1 and Day 7, immediately prior to oral administration of POS. POS trough samples were also obtained immediately prior to dosing on Days 3, 5, 8, 14, AND 28 or within 24 hours after the last dose of study drug for earlier discontinuations.

Fig 2. Subject disposition.

* Of the 6 subjects not treated, 4 subjects did not wish to continue due to reasons unrelated to assigned study treatment, 1 subject did not meet protocol eligibility, and 1 subject had an adverse event (AE). # Most common reasons for discontinuation of the treatment phase were: AE (n = 35), subject not willing to continue due to reasons unrelated to treatment (n = 7), subject not meeting protocol requirement to continue therapy (due to recovery from neutropenia before 7 days of therapy, n = 4) and non-compliance with protocol (n = 3). ± Three subjects discontinued follow up due to an AE, and one subject was non-compliant with the protocol.

Fig 3. Combined Mean plasma concentration profile by age group and dosing cohort following single (day 1) and multiple dose (day 7) administration of posaconazole oral suspension.