TY - JOUR
T1 - Safety and Pharmacokinetic Study of Fidaxomicin in Children With Clostridium difficile-Associated Diarrhea
T2 - A phase 2A multicenter clinical trial
AU - O'Gorman, Molly A.
AU - Michaels, Marian G.
AU - Kaplan, Sheldon L.
AU - Otley, Anthony
AU - Kociolek, Larry K.
AU - Hoffenberg, Edward J.
AU - Kim, Kwang Sik
AU - Nachman, Sharon
AU - Pfefferkorn, Marian D.
AU - Sentongo, Timothy
AU - Sullivan, Janice E.
AU - Sears, Pamela
N1 - Funding Information:
Acknowledgments. We thank the investigators and their staff: R. L. Debiasi, J. G. Deville, A. Forbes, N. Jeffrey, J. C. McNeil, D. Speicher, J. Stamos, R. Steele, and J. Vallejo. We also thank S. L. Gorbach (formerly of Optimer Pharmaceuticals) for input into the design and conduct of this study. Medical writing assistance was provided by Laura Fullerton-Batten of Complete Medical Communications (Macclesfield, United Kingdom) and Walter Rozdilsky of Complete Medical Communications (Hackensack, NJ). This assistance was funded by Merck & Co., Inc. (Kenilworth, NJ).
Funding Information:
Financial support. Funding for this research was provided by Merck & Co., Inc. (Kenilworth, NJ).
Funding Information:
Potential conflicts of interest. L. K. K. has received a research grant from Merck and research support (supplies) from Alere/Techlab and is a scientific advisor for Actelion. M. D. P. currently has a research grant from Astellas to study fidaxomicin versus vancomycin in CDAD. P. S. is an employee of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., (Kenilworth, NJ) and owns stock/stock options in the company. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.
Publisher Copyright:
© The Author(s) 2017. Published by Oxford University Press on behalf of The Journal of the Pediatric Infectious Diseases Society.
Copyright:
Copyright 2021 Elsevier B.V., All rights reserved.
PY - 2018/8/17
Y1 - 2018/8/17
N2 - Background: Fidaxomicin is an approved therapy for Clostridium difficile-associated diarrhea (CDAD) in adults. The safety of fidaxomicin in children has not been reported. Methods: In this study (ClinicalTrials.gov identifier NCT01591863), pediatric patients with CDAD received twice-daily oral fidaxomicin at a dose of 16 mg/kg per day (up to 200 mg) for 10 days in an open-label study. Plasma and fecal samples were collected for pharmacokinetic assessments. The primary outcome measure was safety, which was assessed by adverse-event (AE), laboratory, and physical examination/vital-sign monitoring. Efficacy was determined through early and sustained clinical response rates (clinical response without recurrence of CDAD). Results: The study enrolled 40 patients (11 months to 17 years of age), many with underlying comorbidity, including neoplasm (23.7%), gastrointestinal disorder (78.9%), and history of CDAD (60.5%). Plasma fidaxomicin and OP-1118 (the major fidaxomicin metabolite) 3- to 5-hour postdose concentrations were 0.6 to 87.4 and 2.4 to 882.0 ng/mL, respectively, and no age-related trends were seen. Fecal fidaxomicin concentrations within 24 hours of the last dose averaged 3228 µg/g, and higher concentrations and greater variability in the youngest age group were found. AEs were reported in 73.7% of the patients; most of them were mild (44.7%) to moderate (21.1%) and were considered treatment-related in 15.8% of the patients. Overall, the early clinical response rate was 92.1%. The rate of sustained clinical response (clinical response without recurrence through 28 days after treatment) was 65.8% overall. Conclusions: Fidaxomicin was well tolerated in children with CDAD and has a pharmacokinetic profile in children similar to that in adults. The clinical response rate was high.
AB - Background: Fidaxomicin is an approved therapy for Clostridium difficile-associated diarrhea (CDAD) in adults. The safety of fidaxomicin in children has not been reported. Methods: In this study (ClinicalTrials.gov identifier NCT01591863), pediatric patients with CDAD received twice-daily oral fidaxomicin at a dose of 16 mg/kg per day (up to 200 mg) for 10 days in an open-label study. Plasma and fecal samples were collected for pharmacokinetic assessments. The primary outcome measure was safety, which was assessed by adverse-event (AE), laboratory, and physical examination/vital-sign monitoring. Efficacy was determined through early and sustained clinical response rates (clinical response without recurrence of CDAD). Results: The study enrolled 40 patients (11 months to 17 years of age), many with underlying comorbidity, including neoplasm (23.7%), gastrointestinal disorder (78.9%), and history of CDAD (60.5%). Plasma fidaxomicin and OP-1118 (the major fidaxomicin metabolite) 3- to 5-hour postdose concentrations were 0.6 to 87.4 and 2.4 to 882.0 ng/mL, respectively, and no age-related trends were seen. Fecal fidaxomicin concentrations within 24 hours of the last dose averaged 3228 µg/g, and higher concentrations and greater variability in the youngest age group were found. AEs were reported in 73.7% of the patients; most of them were mild (44.7%) to moderate (21.1%) and were considered treatment-related in 15.8% of the patients. Overall, the early clinical response rate was 92.1%. The rate of sustained clinical response (clinical response without recurrence through 28 days after treatment) was 65.8% overall. Conclusions: Fidaxomicin was well tolerated in children with CDAD and has a pharmacokinetic profile in children similar to that in adults. The clinical response rate was high.
KW - Clostridium difficile infection
KW - Clostridium difficile-associated diarrhea
KW - Fidaxomicin
KW - Pediatrics
KW - Pharmacokinetics
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U2 - 10.1093/jpids/pix037
DO - 10.1093/jpids/pix037
M3 - Article
C2 - 28575523
AN - SCOPUS:85049639760
SN - 2048-7193
VL - 7
SP - 210
EP - 218
JO - Journal of the Pediatric Infectious Diseases Society
JF - Journal of the Pediatric Infectious Diseases Society
IS - 3
ER -