Probability of Optimal Target Attainment of Amikacin in Patients With Febrile Neutropenia During Treatment for a Hematological Disorder

Probability of Optimal Target Attainment of Amikacin in Patients With Febrile Neutropenia During Treatment for a Hematological Disorder: a Prospective, Single-centre Study and PKPD-analysis

The present trial is a single center, prospective, observational pharmacokinetics and pharmacodynamics (PKPD) cohort study investigating whether patients suffering from a hematological disorder and treated with amikacin due to febrile neutropenia (FN) achieve the predefined amikacin target concentration (Cmax ≥60 mg/L).

Study Overview

• Status: Completed
• Conditions: Febrile Neutropenia (FN)
• Intervention / Treatment: Other: Data collection: Amikacin concentration

Detailed Description

Amikacin is an aminoglycoside (AG) that exerts a rapid bactericidal effect against many Gram-negative pathogens. Its pharmacological effect depends on the peak concentration achieved. However, a common side effect of AG is dose-dependent acute kidney injury (AKI), especially when administered over several days due to an accumulation of the drug in the proximal renal tubular cells. In patients in advanced stage of a hematological disease, low body weight influences amikacin pharmacokinetics and pharmacodynamics (PKPD) and increases its clearance. However, there is little known about amikacin PKPD in patients with febrile neutropenia (FN). Whereas the therapeutic efficacy is associated with the peak concentration of AG, toxicity of AG depends on the area under the curve (AUC) or trough level of the drug. When using the AUC to predict renal toxicity, an AUC between 200 and 300 mg/L * h of amikacin has been proposed as a potential threshold for renal toxicity. At the University Hospital Basel (USB), amikacin is administered intravenously (iv) as once daily infusion combined with cefepime or piperacillin/tazobactam immediately after the occurrence of a fever spike in patients with FN. After the iv administration of amikacin, peak concentration is achieved after 30-60 min. The in-house guidelines recommend the administration of lower amikacin dosages compared to other published studies (15 mg/kg body weight vs. 20 mg/kg or up to 30 mg/kg). It remains unclear if adequate peak concentrations are achieved in patients with FN, when lower amikacin doses are administered. The aim of this study is to investigate the probability of optimal pharmacological target attainment (Cmax ≥60 mg/L) during amikacin treatment among patients with FN treated for hematological disorder in order to evaluate the in-house amikacin dosage recommendations. The current project includes the sampling of biological material during hospital admission and the collection of health-related personal data.

• Study Type: Observational
• Enrollment (Actual): 92

Contacts and Locations

Study Locations

• Switzerland
  • Basel, Switzerland, 4031
    • University Hospital Basel, Division of Internal Medicine

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

• Sampling Method: Probability Sample

Study Population

Inpatients being at risk of developing FN after treatment for a hematological disorder, admitted to the Department of Internal Medicine or the Department of Hematology at the University Hospital Basel (USB) and who are intended to receive amikacin iv during their hospital stay will be screened for eligibility.

Description

Inclusion Criteria:

• Age ≥ 18 years
• Informed consent (IC) as documented by signature
• Documented hematological disorder
• Hospitalization at the USB due to the treatment for a hematological disorder (e.g. chemotherapy, stem cell transplantation)
• Being at risk of developing FN during the hospital stay (e.g. because of chemotherapy)

Exclusion Criteria:

• Previous enrolment into the current study
• Outpatients
• Patients undergoing hemodialysis
• Women who are pregnant (special pharmacokinetic)

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in pharmacological target attainment (Cmax ≥60 mg/L) in blood during amikacin treatment	Percentage of patients with optimal pharmacological target attainment (Cmax ≥60 mg/L) in blood during amikacin treatment	60 minutes (+/-30 minutes) and 8 hours (+/-1 hour) after the beginning of amikacin infusion on day 1, day 2 and day 3

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
AUC >200 mg/L and AUC >300 mg/L* h during amikacin treatment	Percentage of patients achieving the threshold of potential renal toxicity defined as AUC >200 mg/L and AUC >300 mg/L* h respectively during amikacin treatment	Up to 3 days after the beginning of amikacin infusion
Percentage of patients achieving a calculated Cmin <4 mg/L in blood	Percentage of patients achieving a calculated Cmin <4 mg/L in blood during amikacin treatment	Up to 3 days after the beginning of amikacin infusion
Incidence of Acute kidney injury (AKI)	Incidence of AKI	Within 7 days after application of amikacin
Percentage of patients with optimal pharmacological target attainment	Percentage of patients with optimal pharmacological target attainment using a Cmax/minimal inhibitory concentration (MIC) ≥8 in patients with an identified causative pathogen	Up to 3 days after the beginning of amikacin infusion
Time interval between the detection of the first fever spike and the administration of amikacin	Time interval between the detection of the first fever spike and the administration of amikacin	One time assessment at baseline (Day 1)

Collaborators and Investigators

• Sponsor: University Hospital, Basel, Switzerland
• Investigators: Principal Investigator: Michael Osthoff, PD Dr. med., University Hospital Basel, Division of Internal Medicine

Study record dates

Study Major Dates

• Study Start (Actual): December 21, 2022
• Primary Completion (Actual): February 2, 2024
• Study Completion (Actual): February 2, 2024

Study Registration Dates

• First Submitted: January 4, 2023
• First Submitted That Met QC Criteria: January 9, 2023
• First Posted (Actual): January 19, 2023

Study Record Updates

• Last Update Posted (Estimated): February 21, 2024
• Last Update Submitted That Met QC Criteria: February 20, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Keywords: Amikacin; Acute kidney injury (AKI); Hematological disorder; Aminoglycoside (AG); Area under the curve (AUC); Pharmacokinetics and pharmacodynamics (PKPD) analysis; Peak serum concentration (Cmax); Trough serum concentration (Cmin); Renal toxicity; Pharmacological target attainment; Amikacin concentration
• Additional Relevant MeSH Terms: Wounds and Injuries; Agranulocytosis; Leukopenia; Leukocyte Disorders; Body Temperature Changes; Heat Stress Disorders; Neutropenia; Hematologic Diseases; Hyperthermia; Fever; Febrile Neutropenia; Anti-Infective Agents; Anti-Bacterial Agents; Amikacin
• Other Study ID Numbers: 2022-01218; am23Osthoff

Drug and device information, study documents

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