Safety and Pharmacokinetic Study of Fidaxomicin in Children With Clostridium difficile-Associated Diarrhea: A phase 2A multicenter clinical trial

Molly A. O'Gorman, Marian G. Michaels, Sheldon L. Kaplan, Anthony Otley, Larry K. Kociolek, Edward J. Hoffenberg, Kwang Sik Kim, Sharon Nachman, Marian Pfefferkorn, Timothy Sentongo, Janice E. Sullivan, Pamela Sears

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)210-218
Number of pages9
JournalJournal of the Pediatric Infectious Diseases Society
Volume7
Issue number3
DOIs
StatePublished - Jan 1 2018

Fingerprint

Clostridium difficile
Multicenter Studies
Diarrhea
Pharmacokinetics
Clinical Trials
Safety
Recurrence
Gastrointestinal Neoplasms
Vital Signs
lipiarmycin
Physical Examination
Comorbidity
Therapeutics
Age Groups
Outcome Assessment (Health Care)
Pediatrics

Keywords

  • Clostridium difficile infection
  • Clostridium difficile-associated diarrhea
  • Fidaxomicin
  • Pediatrics
  • Pharmacokinetics

ASJC Scopus subject areas

  • Pediatrics, Perinatology, and Child Health
  • Infectious Diseases

Cite this

Safety and Pharmacokinetic Study of Fidaxomicin in Children With Clostridium difficile-Associated Diarrhea : A phase 2A multicenter clinical trial. / O'Gorman, Molly A.; Michaels, Marian G.; Kaplan, Sheldon L.; Otley, Anthony; Kociolek, Larry K.; Hoffenberg, Edward J.; Kim, Kwang Sik; Nachman, Sharon; Pfefferkorn, Marian; Sentongo, Timothy; Sullivan, Janice E.; Sears, Pamela.

In: Journal of the Pediatric Infectious Diseases Society, Vol. 7, No. 3, 01.01.2018, p. 210-218.

Research output: Contribution to journalArticle

O'Gorman, MA, Michaels, MG, Kaplan, SL, Otley, A, Kociolek, LK, Hoffenberg, EJ, Kim, KS, Nachman, S, Pfefferkorn, M, Sentongo, T, Sullivan, JE & Sears, P 2018, 'Safety and Pharmacokinetic Study of Fidaxomicin in Children With Clostridium difficile-Associated Diarrhea: A phase 2A multicenter clinical trial', Journal of the Pediatric Infectious Diseases Society, vol. 7, no. 3, pp. 210-218. https://doi.org/10.1093/jpids/pix037
O'Gorman, Molly A. ; Michaels, Marian G. ; Kaplan, Sheldon L. ; Otley, Anthony ; Kociolek, Larry K. ; Hoffenberg, Edward J. ; Kim, Kwang Sik ; Nachman, Sharon ; Pfefferkorn, Marian ; Sentongo, Timothy ; Sullivan, Janice E. ; Sears, Pamela. / Safety and Pharmacokinetic Study of Fidaxomicin in Children With Clostridium difficile-Associated Diarrhea : A phase 2A multicenter clinical trial. In: Journal of the Pediatric Infectious Diseases Society. 2018 ; Vol. 7, No. 3. pp. 210-218.
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abstract = "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.",
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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

AU - Sentongo, Timothy

AU - Sullivan, Janice E.

AU - Sears, Pamela

PY - 2018/1/1

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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.

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KW - Pharmacokinetics

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