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A meropenem pharmacokinetics model in patients with haematological malignancies
A Contejean1,2, L Jaffrelot3, S Benaboud4,3
1Service d'Hématologie, AP-HP, Hôpital Cochin, Paris, France.
Background:
Optimal dosing of antibiotics is critical in immunocompromised patients suspected to have an infection. Data on pharmacokinetics (PK) of meropenem in patients with haematological malignancies are scarce.
Objectives:
To optimize dosing regimens, we aimed to develop a PK population model for meropenem in this population.
Methods:
Patients aged ≥18 years, hospitalized in the haematology department of our 1500 bed university hospital for a malignant haematological disease and who had received at least one dose of meropenem were eligible. Meropenem was quantified by HPLC. PK were described using a non-linear mixed-effect model and external validation performed on a distinct database. Monte Carlo simulations estimated the PTA, depending on renal function, duration of infusion and MIC. Target for free trough concentration was set at >4× MIC.
Results:
Overall, 88 patients (181 samples) were included, 66 patients (75%) were in aplasia and median Modification of Diet in Renal Disease (MDRD) CLCR was 117 mL/min/1.73 m2 (range: 35-359). Initial meropenem dosing regimen ranged from 1 g q8h to 2 g q8h over 30 to 60 min. A one-compartment model with first-order elimination adequately described the data. Only MDRD CLCR was found to be significantly associated with CL. Only continuous infusion achieved a PTA of 100% whatever the MIC and MDRD CLCR. Short duration of infusion (<60 min) failed to reach an acceptable PTA, except for bacteria with MIC < 0.25 mg/L in patients with MDRD CLCR below 90 mL/min/1.73 m2.
Conclusions:
In patients with malignant haematological diseases, meropenem should be administered at high dose (6 g/day) and on continuous infusion to reach acceptable trough concentrations.
Insights
Optimal meropenem dosing is crucial for immunocompromised patients with hematological malignancies. Continuous infusion at high doses (6 g/day) ensures effective antibiotic exposure, achieving 100% target attainment regardless of renal function or MIC.
Area of Science:
- Pharmacology
- Infectious Diseases
- Hematology
Background:
- Optimal antibiotic dosing is critical for immunocompromised patients with suspected infections.
- Limited pharmacokinetic data exists for meropenem in patients with hematological malignancies.
Purpose of the Study:
- To develop a pharmacokinetic (PK) population model for meropenem in patients with hematological malignancies.
- To optimize meropenem dosing regimens for this vulnerable patient group.
Main Methods:
- A non-linear mixed-effect model was used to describe meropenem PK in 88 adult patients with hematological malignancies.
- High-performance liquid chromatography (HPLC) quantified meropenem levels.
- Monte Carlo simulations assessed probability of target attainment (PTA) based on renal function, infusion duration, and minimum inhibitory concentration (MIC).
Main Results:
- A one-compartment model adequately described meropenem PK, with MDRD CLCR significantly associated with clearance.
- Continuous infusion achieved 100% PTA for all MICs and renal function levels.
- Short infusions (<60 min) were insufficient unless MIC was <0.25 mg/L and MDRD CLCR was <90 mL/min/1.73 m².
Conclusions:
- High-dose meropenem (6 g/day) administered via continuous infusion is recommended for patients with malignant hematological diseases.
- This strategy ensures acceptable drug concentrations and optimizes treatment outcomes.
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