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Therapeutic drug monitoring of posaconazole oral suspension in paediatric patients younger than 13 years of age: a retrospective analysis and literature review.

ABSTRACT: WHAT IS KNOWN AND OBJECTIVE:Posaconazole is an extended-spectrum triazole antifungal with activity against a variety of clinically significant yeasts and moulds. Posaconazole is not currently approved by the U.S. Food and Drug Administration for use in children younger than 13 years of age. Our primary objective was to describe the dosing and observed trough concentrations with posaconazole oral suspension in paediatric patients at the National Institutes of Health Clinical Center (Bethesda, MD). METHODS:This retrospective single-centre study reviewed paediatric patients younger than 13 years of age initiated on posaconazole oral suspension. Patients were included if they were initiated on posaconazole for prophylaxis or treatment for fungal infections from September 2006 through March 2013 with at least one trough concentration collected after at least 7 days of therapy. RESULTS AND DISCUSSION:A total of 20 male patients were included, of whom 15 (75%) had chronic granulomatous disease. The median age of patients was 6·5 years (range: 2·8-10·7). A total of 79 posaconazole trough concentrations were measured in patients receiving posaconazole as prophylaxis (n = 8) or treatment (n = 12). Posaconazole dose referenced to total body weight ranged from 10·0 to 49·2 mg/kg/day. Posaconazole trough concentrations ranged from undetectable (<50 ng/mL) up to 3620 ng/mL and were ?500, ?700 and ?1250 ng/mL in 95%, 60% and 25% of patients, respectively. WHAT IS NEW AND CONCLUSIONS:Patients younger than 13 years of age had highly variable trough concentrations, and recommendations for the appropriate dosing of posaconazole oral suspension remain challenging. Until studies are conducted to determine the appropriate dosing of posaconazole in this patient population, therapeutic drug monitoring should be considered to ensure adequate posaconazole exposure.

SUBMITTER: Jancel T

PROVIDER: S-EPMC5209268 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature

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Therapeutic drug monitoring of posaconazole oral suspension in paediatric patients younger than 13 years of age: a retrospective analysis and literature review.

Jancel T T Shaw P A PA Hallahan C W CW Kim T T Freeman A F AF Holland S M SM Penzak S R SR

Journal of clinical pharmacy and therapeutics 20161216 1

<h4>What is known and objective</h4>Posaconazole is an extended-spectrum triazole antifungal with activity against a variety of clinically significant yeasts and moulds. Posaconazole is not currently approved by the U.S. Food and Drug Administration for use in children younger than 13 years of age. Our primary objective was to describe the dosing and observed trough concentrations with posaconazole oral suspension in paediatric patients at the National Institutes of Health Clinical Center (Bethe ...[more]

PMID: 27982447

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Project description: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.

Project description:Abstract 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 Cavg and individual Cavg ≥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 Cavg generally met PK targets. Model-predicted Cavg was ≥500 ng/mL in >90% of subjects in all cohorts. The 1200-ng/mL target geometric mean Cavg 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. Disclosures All authors: No reported disclosures.

Project description:BACKGROUND:There is increasing availability of, and interest in, wearable activity trackers for children younger than 13 years. However, little is known about how children and parents use these activity trackers or perceive their acceptability. OBJECTIVE:This study primarily aimed to ascertain parental perspectives on the acceptability and usability of wearables designed to monitor children's physical activity levels. Secondary aims were to (1) identify practical considerations for future use in physical activity interventions and promotion initiatives; (2) determine use of different features and functions incorporated into the accompanying app; and (3) identify parents' awareness of their child's current physical activity levels. METHODS:In total, 36 children (18 boys and 18 girls) aged 7-12 years were asked to wear a wrist-worn activity tracker (KidFit) for 4 consecutive weeks and to use the accompanying app with parental assistance and guidance. Each week, one parent from each family (n=25; 21 mothers and 4 fathers) completed a Web-based survey to record their child's activity tracker use, app interaction, and overall experiences. At the end of the 4-week period, a subsample of 10 parents (all mothers) participated in face-to-face interviews exploring perceptions of the acceptability and usability of wearable activity trackers and accompanying apps. Quantitative and qualitative data were analyzed descriptively and thematically, respectively. Thematic data are presented using pen profiles, which were constructed from verbatim transcripts. RESULTS:Parents reported that they and their children typically found the associated app easy to use for activity tracking, though only step or distance information was generally accessed and some difficulties interpreting the data were reported. Children were frustrated with not being able to access real-time feedback, as the features and functions were only available through the app, which was typically accessed by, or in the presence of, parents. Parents identified that children wanted additional functions including a visual display to track and self-monitor activity, access to the app for goal setting, and the option of undertaking challenges against schools or significant others. Other barriers to the use of wearable activity trackers included discomfort of wearing the monitor because of the design and the inability to wear for water- or contact-based sports. CONCLUSIONS:Most parents reported that the wearable activity tracker was easy for their child or children to use and a useful tool for tracking their children's daily activity. However, several barriers were identified, which may impact sustained use over time; both the functionality and wearability of the activity tracker should therefore be considered. Overall, wearable activity trackers for children have the potential to be integrated into targeted physical activity promotion initiatives.

Dataset Information

Therapeutic drug monitoring of posaconazole oral suspension in paediatric patients younger than 13 years of age: a retrospective analysis and literature review.

Publications

Therapeutic drug monitoring of posaconazole oral suspension in paediatric patients younger than 13 years of age: a retrospective analysis and literature review.

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