Population Pharmacokinetics of Amikacin in Neonates

Population Pharmacokinetics of Amikacin in Suspected Cases of Neonatal Sepsis: Multicenter Study

Aminoglycosides such as Amikacin are routinely used in newborns for the treatment of neonatal sepsis due to gram-negative bacilli. Despite the frequency of this indication, it has not yet been possible to establish definitive dosage schedules that ensure effectiveness and low risk of toxicity, due to the high pharmacokinetic variability observed in this population.

In addition to anthropometric variables, evidence from retrospective studies suggests that sepsis could be capable of significantly modifying the pharmacokinetics of aminoglycosides in neonates, but the investigators suggest conducting prospective studies of higher methodological quality to verify this hypothesis.

Due to the lack of pharmacokinetic and pharmacodynamic (PK / PD) studies of Amikacin in this group of patients, the investigators have raised the need to develop a prospective observational study; describing a PK / PD model of amikacin in newborns with suspected sepsis.

Study Overview

• Status: Completed
• Conditions: Neonatal Sepsis, Late-Onset
• Intervention / Treatment: Drug: Amikacin Sulfate Injection

Detailed Description

Three blood samples will be taken from each of the 138 participants. As a standard of care, a sample will always be taken at 0.5h (Cmax) after the first dose and a sample before the second dose, which can be at 24h, 36h, or 48h as per physician indication. The third sample will be collected according to what has been assigned by a block randomization method, in one of the following moments: 1, 2, 4, 8, 12 or 18 hours after the administration of the first dose of Amikacin.

The methods used to analyze the samples will be: Particle Enhanced Turbidimetric Immunoassay (PETIA), Architect C8000; and Homogeneous Microparticle Immunoassay in Solution (KIMS), Roche systems. The determination of the susceptibility and minimum Inhibitory Concentration (MIC) will be carried out by the laboratories of each hospital by agar dilution method.

PK/PD profile of amikacin will be evaluated with NONMEM (non-linear mixed effects modelling) software for the analysis.

• Study Type: Observational
• Enrollment (Actual): 138

Contacts and Locations

Study Locations

• Chile
  • Santiago, Chile, 8330024
    • Hospital Clínico UC-Christus

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 3 days to 1 month (CHILD)
• Accepts Healthy Volunteers: N/A
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

Patients admitted to neonatal intensive care units of two hospitals of high-complexity in Chile

Description

Inclusion Criteria:

• Receive at least one dose of Amikacin
• Be at least three days old (72 hours)

Exclusion Criteria:

• Receive the first dose of Amikacin in a healthcare center other than those included in the research
• Patient on renal replacement therapy

Study Plan

How is the study designed?

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
No Sepsis / Sepsis; To compare amikacin PK / PD models of newborns with a confirmed diagnosis of sepsis (clinical or microbiological) and with ruled out sepsis.	Drug: Amikacin Sulfate Injection; The dose and frequency of amikacin was defined by each hospital.; Other Names: Amikacin

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Volume of Distribution (L/Kg) of Amikacin	The mean population parameter and their interindividual variability in neonates with suspected sepsis	first dose amikacin (1 day)
Clearance (L/h) of Amikacin	The mean population parameter and their interindividual variability in neonates with suspected sepsis	first dose amikacin (1 day)
PK/PD targets of amikacin	Peak Plasma Concentration (Cmax) over 8 fold Minimum Inhibitory Concentration (MIC) or Cmax: 24-35 mg/L	first dose amikacin (1 day)

Collaborators and Investigators

• Sponsor: Pontificia Universidad Catolica de Chile
• Investigators: Principal Investigator: Nicolas F Severino, PharmD, Facultad de Medicina. Pontificia Universidad Católica de Chile

Publications and helpful links

General Publications

• Lingvall M, Reith D, Broadbent R. The effect of sepsis upon gentamicin pharmacokinetics in neonates. Br J Clin Pharmacol. 2005 Jan;59(1):54-61. doi: 10.1111/j.1365-2125.2005.02260.x.
• Sherwin CM, Svahn S, Van der Linden A, Broadbent RS, Medlicott NJ, Reith DM. Individualised dosing of amikacin in neonates: a pharmacokinetic/pharmacodynamic analysis. Eur J Clin Pharmacol. 2009 Jul;65(7):705-13. doi: 10.1007/s00228-009-0637-4. Epub 2009 Mar 21.

Study record dates

Study Major Dates

• Study Start (ACTUAL): December 1, 2019
• Primary Completion (ACTUAL): July 31, 2021
• Study Completion (ACTUAL): September 3, 2021

Study Registration Dates

• First Submitted: April 27, 2021
• First Submitted That Met QC Criteria: April 27, 2021
• First Posted (ACTUAL): April 30, 2021

Study Record Updates

• Last Update Posted (ACTUAL): April 7, 2022
• Last Update Submitted That Met QC Criteria: March 29, 2022
• Last Verified: April 1, 2021

More Information

Terms related to this study

• Keywords: Neonate; Amikacin; Neonatal Sepsis; Population Pharmacokinetic
• Additional Relevant MeSH Terms: Pathologic Processes; Infections; Systemic Inflammatory Response Syndrome; Inflammation; Infant, Newborn, Diseases; Sepsis; Neonatal Sepsis; Anti-Infective Agents; Anti-Bacterial Agents; Amikacin
• Other Study ID Numbers: 190325002

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No