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

Abstract

BackgroundPosaconazole (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.MethodsThis 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.ResultsThe 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.ConclusionThe 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 registrationClinicalTrials.gov identifier: NCT01716234

Pharmacokinetics and Pharmacodynamics of Posaconazole

“…While the posaconazole oral formulations are approved in patients older than 13 years (USA) or 18 years (Europe), the intravenous form is only labeled for patients older than 18 years, due to potential toxicity to brain ventricle development observed in juvenile dogs [2,30]. However, many studies have reported its off-label use in pediatric patients, which could be attributed to the promising efficacy and safety profile in adults [132][133][134]. A recent population pharmacokinetic model was developed for 171 pediatric immunocompromised patients aged between 5 month and 18 years receiving one of the oral formulations, with nearly 96% of the samples being obtained after administration of the suspension [70].…”

Pharmacodynamics of Posaconazole in Experimental Invasive Pulmonary Aspergillosis: Utility of Serum Galactomannan as a Dynamic Endpoint of Antifungal Efficacy

“…Based on a set of carefully designed and well executed clinical trials performed during the past two decades (4)(5)(6), the compound has evolved into an important option for prophylaxis and treatment of invasive opportunistic fungal diseases (IFDs) in severely immunocompromised patients. Whereas the usefulness of the initially approved oral suspension was limited by high intra-and interindividual bioavailability (7,8), the subsequently developed delayed release tablet formulation and the parenteral cyclodextrin formulation allow for more controlled administration of the compound (9)(10)(11)(12). Leading international guidelines currently recommend posaconazole for primary antifungal prophylaxis in patients with acute myeloid leukemia/myelodysplastic syndrome and prolonged neutropenia and in patients with acute graft vs. host disease following allogeneic hematopoietic stem cell transplantation, as well as second line therapy for treatment of invasive aspergillosis (13)(14)(15).…”

“…The compound is highly protein bound with serum albumin being the predominant binding protein. Previous studies with the oral suspension have shown that posaconazole exhibits linear elimination with a high apparent volume of distribution, a slow rate of absorption (8), and varying bioavailability. Nevertheless, no distribution into deeper compartments was detectable and a one compartment pharmacokinetic model was used in previous pharmacokinetic analyses (5).…”

Posaconazole delayed‐release tablets in paediatric haematology–oncology patients

“…Invasive fungal infections (IFIs) represent a major cause of morbidity and mortality in high‐risk paediatric haematology‐oncology patients 1‐3 …”

“…The target posaconazole plasma concentrations (PPC) used for adult patients (≥0.7 μg/mL for prophylaxis and ≥1 μg/mL for treatment) are used also for children, although even subtherapeutic levels have showed a prophylactic effect 6‐8 . The therapeutic drug monitoring (TDM) of posaconazole is recommended, especially in paediatric patients 3,7,9,10,11 . To date, there are few studies that describe pharmacokinetics, safety and efficacy of posaconazole DRT formulation in paediatric population.…”