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1558. A Population Pharmacokinetic Model for Posaconazole Intravenous Solution and Oral Powder for Suspension Formulations in Pediatric Patients With Neutropenia
BACKGROUND: Posaconazole is approved in adults for prophylaxis and treatment of invasive fungal disease. Two formulations that offer weight-based dosing—intravenous (IV) and oral powder for suspension (PFS)—are being evaluated in children. A population pharmacokinetic (popPK) approach was used to ch...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Oxford University Press
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6808851/ http://dx.doi.org/10.1093/ofid/ofz360.1422 |
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author | Winchell, Gregory A de Greef, Rik Wrishko, Rebecca E Mangin, Eric Waskin, Hetty Bruno, Christopher |
author_facet | Winchell, Gregory A de Greef, Rik Wrishko, Rebecca E Mangin, Eric Waskin, Hetty Bruno, Christopher |
author_sort | Winchell, Gregory A |
collection | PubMed |
description | BACKGROUND: Posaconazole is approved in adults for prophylaxis and treatment of invasive fungal disease. Two formulations that offer weight-based dosing—intravenous (IV) and oral powder for suspension (PFS)—are being evaluated in children. A population pharmacokinetic (popPK) approach was used to characterize and predict the PK exposure of posaconazole PFS and IV formulations in children to identify dosages associated with achieving a target PK of 1200 ng/mL as the mean C(avg) and individual C(avg) ≥500 ng/mL and <2500 ng/mL in ~90% of patients. METHODS: A popPK model was developed through nonlinear mixed-effects modeling using data obtained from a trial in children with neutropenia (ClinicalTrials.gov, NCT02452034; Merck protocol, MK-5592-097). Three dose cohorts (3.5, 4.5, and 6 mg/kg/day [≤300 mg/day]) were studied in two age groups (2–<7 years and 7–17 years). Posaconazole IV was administered twice on day 1 then once daily through at least day 10, followed by PFS once daily through day 28 at clinician discretion. A compartmental model, including both formulations, was fit to the data. Model selection was based on the Log-Likelihood Criterion, goodness-of-fit plots, and scientific plausibility. Significance of the covariates was assessed in a stepwise forward inclusion/backward procedure. An additional assessment characterized the impact of different food covariates on bioavailability. RESULTS: An open one-compartmental PK model with first-order absorption and estimated bioavailability, as well as allometrically scaled effects of body weight on clearance and volume, adequately described the PK of posaconazole IV and PFS formulations. Model predictions are shown in the Table. Effects of the different food covariates were not statistically significant. Simulations indicated that for the 6-mg/kg/d dose, model-predicted C(avg) generally met PK targets. Model-predicted C(avg) was ≥500 ng/mL in >90% of subjects in all cohorts. The 1200-ng/mL target geometric mean C(avg) was achieved for all but the 2–<7 years cohort receiving the PFS formulation. CONCLUSION: This popPK-based analysis demonstrated that the 6-mg/kg/d dose of IV or PFS posaconazole formulation (≤300 mg/days) is appropriate for children (2–17 years) and that PFS can be administered without regard to food. [Image: see text] DISCLOSURES: All authors: No reported disclosures. |
format | Online Article Text |
id | pubmed-6808851 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Oxford University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-68088512019-10-28 1558. A Population Pharmacokinetic Model for Posaconazole Intravenous Solution and Oral Powder for Suspension Formulations in Pediatric Patients With Neutropenia Winchell, Gregory A de Greef, Rik Wrishko, Rebecca E Mangin, Eric Waskin, Hetty Bruno, Christopher Open Forum Infect Dis Abstracts BACKGROUND: Posaconazole is approved in adults for prophylaxis and treatment of invasive fungal disease. Two formulations that offer weight-based dosing—intravenous (IV) and oral powder for suspension (PFS)—are being evaluated in children. A population pharmacokinetic (popPK) approach was used to characterize and predict the PK exposure of posaconazole PFS and IV formulations in children to identify dosages associated with achieving a target PK of 1200 ng/mL as the mean C(avg) and individual C(avg) ≥500 ng/mL and <2500 ng/mL in ~90% of patients. METHODS: A popPK model was developed through nonlinear mixed-effects modeling using data obtained from a trial in children with neutropenia (ClinicalTrials.gov, NCT02452034; Merck protocol, MK-5592-097). Three dose cohorts (3.5, 4.5, and 6 mg/kg/day [≤300 mg/day]) were studied in two age groups (2–<7 years and 7–17 years). Posaconazole IV was administered twice on day 1 then once daily through at least day 10, followed by PFS once daily through day 28 at clinician discretion. A compartmental model, including both formulations, was fit to the data. Model selection was based on the Log-Likelihood Criterion, goodness-of-fit plots, and scientific plausibility. Significance of the covariates was assessed in a stepwise forward inclusion/backward procedure. An additional assessment characterized the impact of different food covariates on bioavailability. RESULTS: An open one-compartmental PK model with first-order absorption and estimated bioavailability, as well as allometrically scaled effects of body weight on clearance and volume, adequately described the PK of posaconazole IV and PFS formulations. Model predictions are shown in the Table. Effects of the different food covariates were not statistically significant. Simulations indicated that for the 6-mg/kg/d dose, model-predicted C(avg) generally met PK targets. Model-predicted C(avg) was ≥500 ng/mL in >90% of subjects in all cohorts. The 1200-ng/mL target geometric mean C(avg) was achieved for all but the 2–<7 years cohort receiving the PFS formulation. CONCLUSION: This popPK-based analysis demonstrated that the 6-mg/kg/d dose of IV or PFS posaconazole formulation (≤300 mg/days) is appropriate for children (2–17 years) and that PFS can be administered without regard to food. [Image: see text] DISCLOSURES: All authors: No reported disclosures. Oxford University Press 2019-10-23 /pmc/articles/PMC6808851/ http://dx.doi.org/10.1093/ofid/ofz360.1422 Text en © The Author(s) 2019. Published by Oxford University Press on behalf of Infectious Diseases Society of America. http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence (http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any medium, provided the original work is not altered or transformed in any way, and that the work is properly cited. For commercial re-use, please contact journals.permissions@oup.com |
spellingShingle | Abstracts Winchell, Gregory A de Greef, Rik Wrishko, Rebecca E Mangin, Eric Waskin, Hetty Bruno, Christopher 1558. A Population Pharmacokinetic Model for Posaconazole Intravenous Solution and Oral Powder for Suspension Formulations in Pediatric Patients With Neutropenia |
title | 1558. A Population Pharmacokinetic Model for Posaconazole Intravenous Solution and Oral Powder for Suspension Formulations in Pediatric Patients With Neutropenia |
title_full | 1558. A Population Pharmacokinetic Model for Posaconazole Intravenous Solution and Oral Powder for Suspension Formulations in Pediatric Patients With Neutropenia |
title_fullStr | 1558. A Population Pharmacokinetic Model for Posaconazole Intravenous Solution and Oral Powder for Suspension Formulations in Pediatric Patients With Neutropenia |
title_full_unstemmed | 1558. A Population Pharmacokinetic Model for Posaconazole Intravenous Solution and Oral Powder for Suspension Formulations in Pediatric Patients With Neutropenia |
title_short | 1558. A Population Pharmacokinetic Model for Posaconazole Intravenous Solution and Oral Powder for Suspension Formulations in Pediatric Patients With Neutropenia |
title_sort | 1558. a population pharmacokinetic model for posaconazole intravenous solution and oral powder for suspension formulations in pediatric patients with neutropenia |
topic | Abstracts |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6808851/ http://dx.doi.org/10.1093/ofid/ofz360.1422 |
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