Safety, Tolerability, and Pharmacokinetics of Posaconazole Oral Suspension in Neutropenic Children

Ref ID: 19303

Author:

A. Arrieta, L. Sung, F. Berthold, A. H. Groll, T. Lehrnbecher, J. Bradley, C. M. Zwaan, J. Li, H. Waskin, M. Walker, N. Kartsonis, A. Paschke, T. J. Walsh

Author address:

Pediatric Posaconazole Study Group, Whitehouse Station, NJ; Merck, Whitehouse Station, NJ.

Full conference title:

53rd Interscience Conference on Antimicrobial Agents and Chemotherapy

Date: 10 September 2014

Abstract:

Background: Posaconazole (POS) is a potent triazole antifungal agent approved in adults for treatment and prophylaxis of invasive fungal infections (IFI). Pharmacokinetic (PK) data are limited for the pediatric population, and thus, dosing is uncertain. In this first clinical trial of POS in pediatric patients, the objective was to evaluate the PK, safety and tolerability of POS oral suspension in children aged 3 months-<18 years with neutropenia or expected neutropenia (ANC 8804;500/mm3). Target POS PK exposure is a mean steady state Cavg exposure of ~1200 ng/mL with ~90% of subjects with Cavg 500-2500 ng/mL, where Cavg is defined as AUC over 24h. Methods: This is a nonrandomized, multicenter, open-label, sequential dose-escalation study. Enrolled children are divided into 3 age groups (AG1, 2-<7 years; AG2, 7-<18 years; AG3, 3 months to <2 years). AG1 and AG2 are divided into three dosage groups (DG): DG1, 12 mg/kg/day divided BID; DG2, 18 mg/kg/day divided BID; and DG3, dosage to be determined from Cavg in DG1 and DG2. AG3 enrollment is being held pending the current analysis of DG1/DG2 in AG1/AG2. Patients received 7-28 days of POS. Extensive PK samples were collected at Days 1 and 7 and trough samples were collected on Days 3, 5, 8, 14, and 28. Results: Preliminary PK results in AG1 and AG2 (n=43) showed that the target exposure was achieved in 52% of subjects in DG1 (n=25; age groups combined) and 56% of subjects in DG2 (n=18). High variability was observed among exposures within each age and dosage cohort; the range in Cavg for DG1 was 34.6-3350 ng/mL and 48.3-4660 ng/mL for DG2. The median Cavg increased by 28% in AG1 but did not increase in AG2. POS was well tolerated in DG1 and DG2 with adverse events generally related to underlying diseases and concomitant therapies.Conclusion: The study suggests that POS 12 and 18 mg/kg/d divided BID failed to achieve the PK exposure target. Observed variability in exposure is likely due to the effect of food intake on POS. Dividing the daily dose TID may enhance PK exposure. We plan to evaluate 18 mg/kg/day divided TID in AG1 and AG2. Two TID dosage groups are planned for AG3 (12 and 18 mg/kg/day).

Abstract Number: NULL

Conference Year: 2013

Link to conference website: NULL

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