Model-informed Precision Dosing for Linezolid (LINEMAP)

Model-informed Precision Dosing for Linezolid: a Pilot Randomized Clinical Trial

Study Rationale: Previous in vitro and retrospective in vivo studies suggest that optimal linezolid concentrations (between 2 and 7 mg/L) achieve clinical efficacy and microbiological eradication while minimizing side effects like thrombocytopenia and the emergence of resistance. No prospective or randomized clinical trial has confirmed these findings, and there is no consensus on how to adjust linezolid dosing to achieve optimal drug concentrations.

Objectives: The primary objective is to determine if model-informed precision dosing optimizes linezolid dosing to achieve therapeutic trough concentrations compared to a standard dose. Secondary objectives include assessing the PK/PD profile, investigating the prevalence of linezolid resistance among gram-positive bacteria, assessing microbiological resolution of infection, and evaluating the safety and tolerability of linezolid.

Methodology: This study is an open, monocentric pilot randomized controlled trial with two arms: standard dose therapy versus dose adjustment based on model-informed precision dosing using therapeutic drug monitoring and PK/PD targets developed in TMDx software.

Sample Size: 28 patients, 14 in each group. Assumptions are based on only 25% of patients in intensive care achieving the optimal therapeutic range with standard dosing, compared to an expected 80% achieving this with model-informed precision dosing.

Selection Criteria: Adult patients (18+ years) already starting linezolid treatment for gram-positive infections, expected to require treatment beyond the next calendar day. Exclusions include imminent death, expected or confirmed pregnancy, expected linezolid treatment of less than 4 days or more than 4 weeks.

Outcomes: The primary endpoint is defined as the difference in the proportion of patients in the intervention and in the control groups who maintained a trough linezolid concentration of 2 to 7 mg/L on Day 7 and Day 13.

Study Overview

• Status: Not yet recruiting
• Conditions: Gram-Positive Bacterial Infections
• Intervention / Treatment: Drug: Linezolid

• Study Type: Interventional
• Enrollment (Estimated): 28
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Flaminia Olearo, MD; Phone Number: 00491738815647; Email: f.olearo@uke.de
• Study Contact Backup: Name: Dominic Wichmann, Prof; Email: d.wichmann@uke.de

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. ≥ 18 years of age
2. Linezolid treatment is indicated or has been started due to pneumonia, skin or soft tissue infection; the patient has received no more than 2 infusions of 600 mg linezolid each
3. with written informed consent of the patient or
4. with written informed consent of his/her legal representative or
5. after using the option of inclusion via spouse according to § 1358 BGB or
6. after application of the independent consultant procedure
7. Patients of childbearing age: negative pregnancy test

Exclusion Criteria:

1. Patients receiving antibiotics active against Gram-positive bacteria at the same time of linezolid
2. Infection other than pneumonia, skin or soft tissue infection, especially tuberculosis, endocarditis and osteomyelitis
3. Death is deemed imminent and inevitable
4. Pregnancy
5. Lactation/breastfeeding

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Linezolid Dosing based on TDMx; Linezolid dosing based on a model-informed precision dosing (TDMx)	Drug: Linezolid; Linezolid dosing will be adapted according to a model informed precision dosing (TDMx)
Active Comparator: Standard Linezolid dosing; Patient will receive Linezolid at standard dose	Drug: Linezolid; Linezolid dosing will be adapted according to a model informed precision dosing (TDMx)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Through concentration in the target	The primary endpoint is defined as the likehood in achieving a trough linezolid concentration of 2 to 8 mg/L on Day 7	Day 7 of linezolid treatment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pharmacokinetic:	Percentage of the dosing interval while drug concentration remains above the MIC (f%T > MIC)	Day 7 and day 13 of linezolid treatment
Thrombocytopenia	Median variation of platelets count after the start up to end of linezolid treatment	From the start of linezolid treatment and up to 14 days
lactic acidosis and peripheral neuropathy	Frequency of lactic acidosis and peripheral neuropathy	From the start of linezolid treatment and up to 14 days
Microbiology	Time to microbiologic eradication is calculated as the interval between the first isolation of a Gram-positive pathogen causing the infection and the first negative culture from the same type of biological material	From the start of linezolid treatment and up to 14 days
Microbiology	Time to development of resistance to linezolid in Gram-positive bacteria is calculated as the interval in days between the first isolation of a specific bacteria species sensitive to linezolid and the first isolation of the same species showing resistance, in any type of biological material.	From the start of linezolid treatment and up to 14 days
Microbiology	Rate of Relapse of gram-positive infection (growth of the same gram-positive organism in the blood culture or in another primarily site infected up to EOF).	At the end of treatment up to the end of 30 day follow-up

Collaborators and Investigators

• Sponsor: University of Hamburg-Eppendorf

Study record dates

Study Major Dates

• Study Start (Estimated): September 1, 2024
• Primary Completion (Estimated): February 28, 2026
• Study Completion (Estimated): June 30, 2026

Study Registration Dates

• First Submitted: May 24, 2024
• First Submitted That Met QC Criteria: May 30, 2024
• First Posted (Actual): June 6, 2024

Study Record Updates

• Last Update Posted (Actual): June 6, 2024
• Last Update Submitted That Met QC Criteria: May 30, 2024
• Last Verified: May 1, 2024

More Information

Terms related to this study

• Keywords: TDM; Linezolid; PK-PD Model
• Additional Relevant MeSH Terms: Infections; Bacterial Infections and Mycoses; Bacterial Infections; Gram-Positive Bacterial Infections; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Anti-Bacterial Agents; Protein Synthesis Inhibitors; Linezolid
• Other Study ID Numbers: TTU 08.922

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
• product manufactured in and exported from the U.S.: No