Metronidazole Pharmacokinetics (PK) in Premature Infants (PTN_METRO)

Safety and Pharmacokinetics of Multiple Dose Metronidazole in Premature Infants

Yearly in the United States over 500,000 newborns are delivered prematurely. This population is at high risk of catastrophic bowel disease known as necrotizing enterocolitis. Infants with necrotizing enterocolitis are at high risk of death, and survivors are at increased risk of mental retardation. Metronidazole is an antibiotic that is often administered to infants with suspected or confirmed necrotizing enterocolitis. Unfortunately, the appropriate dose of metronidazole in premature infants has not been established and it is likely to be different from older children and adults.

The investigators will investigate the appropriate metronidazole dose in very premature infants by: 1) determining how premature infants eliminate metronidazole from the body and 2) determining the safest and most effective dose of metronidazole in premature infants.

The investigators hypothesis are: 1) The rate of removal of metronidazole will increase with infant maturity and 2) an appropriate metronidazole dosing regimen will result in necessary drug levels to treat bacteria involved in necrotizing enterocolitis.

Study Overview

• Status: Completed
• Conditions: Necrotizing Enterocolitis; Serious Systemic Infections
• Intervention / Treatment: Drug: Metronidazole

• Study Type: Interventional
• Enrollment (Actual): 24
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • California
    • Orange, California, United States, 92868
      • CHOC Children's
  • Kansas
    • Wichita, Kansas, United States, 67214
      • Wesely Medical Center
  • North Carolina
    • Durham, North Carolina, United States, 27715
      • Duke University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 2 months (CHILD)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Gestational age <32 weeks at the time of enrollment.
• Postnatal age <91 days at the time of enrollment.
• Sufficient venous access to permit administration of study medication.
• Infant suspected to have a serious infection and from whom a blood culture has been obtained within 96 hours of study entry.

Exclusion Criteria:

• History of anaphylaxis to metronidazole or other nitroimidazole derivatives (e.g., tinidazole).
• Previous exposure to metronidazole in the week prior to study.
• Previous participation in the study.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Treatment; Intravenous metronidazole loading dose 15 mg/kg followed by 7.5 mg/kg every 12-24 hours	Drug: Metronidazole; Metronidazole will be administered intravenously to premature infants as a 15 mg/kg loading dose followed by maintenance doses of 7.5 mg/kg every 12 hours for infants with >=14 postnatal days and every 24 hours for infants <14 postnatal days.; Other Names: Flagyl

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Area Under the Curve at Steady State	Area under the curve at steady state (AUCss)	pre-dose: 30 min; post-dose:10 min, 3-4,6-8, 12-13, 24-25, 36-37, 48-49, 72-73 hours post dose
Loading Dose Maximum Concentration	Loading Dose Maximum concentration (Cmax)	2-5 days of study drug administration
Loading Dose Minimum Concentration	Loading Dose Minimum Concentration (mg/L)	2-5 days of study drug administration
Multiple Dose Maximum Concentration	Multiple Dose Maximum Concentration (mg/L)	2-5 days of study drug administration
Multiple Dose Minimum Concentration	Multiple Dose Minimum Concentration (mg/L)	2-5 days of study drug administration
Clearance	Clearance (L/h/kg)	2-5 days of study drug administration
Volume of Distribution	Volume of Distribution (L/kg)	2-5 days of study drug administration

Collaborators and Investigators

• Sponsor: Michael Cohen-Wolkowiez
• Collaborators: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD); The Emmes Company, LLC

Publications and helpful links

General Publications

• Cohen-Wolkowiez M, Sampson M, Bloom BT, Arrieta A, Wynn JL, Martz K, Harper B, Kearns GL, Capparelli EV, Siegel D, Benjamin DK Jr, Smith PB; Best Pharmaceuticals for Children Act-Pediatric Trials Network. Determining population and developmental pharmacokinetics of metronidazole using plasma and dried blood spot samples from premature infants. Pediatr Infect Dis J. 2013 Sep;32(9):956-61. doi: 10.1097/INF.0b013e3182947cf8.

Study record dates

Study Major Dates

• Study Start: January 1, 2011
• Primary Completion (ACTUAL): November 1, 2011
• Study Completion (ACTUAL): November 1, 2011

Study Registration Dates

• First Submitted: October 6, 2010
• First Submitted That Met QC Criteria: October 15, 2010
• First Posted (ESTIMATE): October 18, 2010

Study Record Updates

• Last Update Posted (ESTIMATE): February 6, 2014
• Last Update Submitted That Met QC Criteria: January 7, 2014
• Last Verified: January 1, 2014

More Information

Terms related to this study

• Keywords: Metronidazole; Sepsis; Neonate; Premature; Necrotizing enterocolitis
• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Infections; Systemic Inflammatory Response Syndrome; Inflammation; Gastrointestinal Diseases; Gastroenteritis; Intestinal Diseases; Pregnancy Complications; Obstetric Labor Complications; Obstetric Labor, Premature; Sepsis; Premature Birth; Enterocolitis; Enterocolitis, Necrotizing; Anti-Infective Agents; Anti-Bacterial Agents; Antiprotozoal Agents; Antiparasitic Agents; Metronidazole
• Other Study ID Numbers: Pro00024571; HHSN27500003I (OTHER_GRANT: NICHD)