Metronidazole Pharmacokinetics (PK) in Premature Infants

Safety and Pharmacokinetics of Multiple Dose Metronidazole in Premature Infants

Status

Completed

Phases

Phase 1

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT01222585

Acronym

PTN_METRO

Enrollment

Registered

2010-10-18

Start date

2011-01-31

Completion date

2011-11-30

Last updated

2014-02-06

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Necrotizing Enterocolitis, Serious Systemic Infections

Keywords

Metronidazole, Neonate, Premature, Sepsis, Necrotizing enterocolitis

Brief summary

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.

Interventions

DRUGMetronidazole

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.

Study design

Allocation

Intervention model

SINGLE_GROUP

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

No minimum to 90 Days

Healthy volunteers

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.

Design outcomes

Primary

Measure	Time frame	Description
Multiple Dose Maximum Concentration	2-5 days of study drug administration	Multiple Dose Maximum Concentration (mg/L)
Area Under the Curve at Steady State	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	Area under the curve at steady state (AUCss)
Loading Dose Maximum Concentration	2-5 days of study drug administration	Loading Dose Maximum concentration (Cmax)
Loading Dose Minimum Concentration	2-5 days of study drug administration	Loading Dose Minimum Concentration (mg/L)
Multiple Dose Minimum Concentration	2-5 days of study drug administration	Multiple Dose Minimum Concentration (mg/L)
Clearance	2-5 days of study drug administration	Clearance (L/h/kg)
Volume of Distribution	2-5 days of study drug administration	Volume of Distribution (L/kg)

Countries

United States

Participant flow

Participants by arm

Arm	Count
Treatment Intravenous metronidazole loading dose 15 mg/kg followed by 7.5 mg/kg every 12-24 hours	24
Total	24

Baseline characteristics

Characteristic	Treatment
Age, Continuous	25 weeks
Birth Weight	740 grams
Ethnicity (NIH/OMB) Hispanic or Latino	6 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	18 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants
Race (NIH/OMB) Asian	0 Participants
Race (NIH/OMB) Black or African American	7 Participants
Race (NIH/OMB) More than one race	0 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	1 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants
Race (NIH/OMB) White	16 Participants
Region of Enrollment United States	24 participants
Sex: Female, Male Female	16 Participants
Sex: Female, Male Male	8 Participants

Adverse events

Event type	EG000 affected / at risk
deaths Total, all-cause mortality	— / —
other Total, other adverse events	17 / 24
serious Total, serious adverse events	5 / 24

Outcome results

Primary

Area Under the Curve at Steady State

Area under the curve at steady state (AUCss)

Time frame: 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

Population: The PK analysis was conducted using samples from 23 subjects. One subject died soon after the loading dose and was excluded from the analysis. Two subjects had no multiple dose samples. Thus data from 20 subjects were used to estimate this PK parameter.

Arm	Measure	Value (MEDIAN)
Metronidazole IV	Area Under the Curve at Steady State	178.0 mg*hr/L

Primary