Clinical trial NCT03643497: Population Pharmacokinetics of Meropenem and Linezolid in Children With Severe Infectious Diseases
Official title: Population Pharmacokinetics of Meropenem and Linezolid in Children With Severe Infectious Diseases
Study type: OBSERVATIONAL
Overall status: UNKNOWN
Conditions: Children；Infection
Lead sponsor: Beijing Children's Hospital
Sponsor class: OTHER
Collaborators: name: Shandong University
name: Hopital Universitaire Robert-Debre
name: Rennes University Hospital
First posted: 2018-08-22
Enrollment: 800
Sex: ALL
Minimum age (years): 1
Maximum age (years): 18
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Severe infectious children with anti-infectious therapies

Brief summary: This study is based on the hypothesis that the pharmacokinetics of meropenem and linezolid in severe infectious children are different from mild infectious children and adults. The investigators aim to study the population pharmacokinetics of children receiving the meropenem and linezolid for treatment of severe infectious diseases. In this study, the investigators will detect drug concentration in plasma and cerebrospinal fluid by using residual blood samples of blood and cerebrospinal fluid gas analysis and other clinical tests and employ computers for constructing population pharmacokinetic models. In addition, the investigators also want to correlate use of meropenem and linezolid with treatment effectiveness and incidence of adverse effects in children. This novel knowledge will allow better and more rational approaches to the treatment of severe infectious diseases in children. It will also set the foundation for further studies to improve anti- infective drug therapies for severe infectious children.

Detailed description: 1.Establish population pharmacokinetic (PPK) models of meropenem and linezolid in severe infectious children by nonlinear mixed effect modeling (NONMEM).

1. At different time point after meropenem or linezolid administration, plasma and/or cerebrospinal fluid samples of 100 children will be collected from pediatric intensive care unit (PICU) for each drug. The clinical information includes demography, medication, concentration data, blood biochemical parameters and so on.
2. Plasma and cerebrospinal fluid samples will be tested by high performance liquid chromatography (HPLC).
3. PPK models of meropenem and linezolid will be established by NONMEM program.
4. The reliability and stability of the PPK model will be evaluated by 1000 times of Bootstrap procedure and normalized predictive distribution error(NPDE).

2. Evaluation of the clinical feasibility and safety of individualized dosing.

1. According the results of PPK models, the investigators will use dosages recommended in models to cure severe infectious children in prospective studies. For antibiotic drug, 50 children will be collected.
2. The investigators will compare the therapeutic effects and safety between children with conventional therapies and children with individualized therapies in severe infectious diseases, including proportions of children with effective drug concentration, improvement speed of children, liver and kidney functions of children, adverse reactions of drugs and so on

Eligibility criteria: Inclusion Criteria:

* Children (0-18 years old) with anti-infective therapy against severe infectious diseases.
* The anti-infective therapy includes meropenem and linezolid commonly used in children with infectious diseases,
* Children severe infectious diseases include severe pneumonia, sepsis, purulent meningitis and other diseases with severe infection.
* Informed consent signed by the parents and/or guardians

Exclusion Criteria:

* Anti-infective drugs aren't involved in the therapies of children.
* It is unable to provide complete medical records or the current condition cannot accept the study process.
* Patients are allergic to meropenem or linezolid.
* Parents and/or guardians do not agree to participate in this study.

Primary outcomes:
measure: maximum concentration (Cmax)
timeFrame: up to 4 weeks
Secondary outcomes:
measure: time to achieve maximum concentration (Tmax)
timeFrame: up to 4 weeks
measure: absorption rate constant (ka)
timeFrame: up to 4 weeks
measure: elimination rate constant (kel)
timeFrame: up to 4 weeks
measure: half-life (t1/2)
timeFrame: up to 4 weeks
Other outcomes:
Locations:
city: Beijing
country: China
facility: Beijing Children's Hospital of Capital Medical University
Study officials:
affiliation: Beijing Children's Hospital of Capital Medical University
name: Shen A-Dong, Master
role: PRINCIPAL_INVESTIGATOR
affiliation: Beijing Children's Hospital of Capital Medical University
name: Qi Yu-Jie, Master
role: STUDY_DIRECTOR
affiliation: Children's Hospital of Hebei Province;Shandong Provincial Qianfoshan Hospital
name: Zhao Wei, Doctor
role: STUDY_DIRECTOR
References:
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citation: Zhao W, Hill H, Le Guellec C, Neal T, Mahoney S, Paulus S, Castellan C, Kassai B, van den Anker JN, Kearns GL, Turner MA, Jacqz-Aigrain E; TINN Consortium. Population pharmacokinetics of ciprofloxacin in neonates and young infants less than three months of age. Antimicrob Agents Chemother. 2014 Nov;58(11):6572-80. doi: 10.1128/AAC.03568-14. Epub 2014 Aug 25.
citation: Wang Z, Bi J, You D, Tang Y, Liu G, Yu J, Jin Z, Jiang T, Tian X, Qi H, Dong L, Dong L, Zhang Q, Zhao W, Shen A. Improving the efficacy for meropenem therapy requires a high probability of target attainment in critically ill infants and children. Front Pharmacol. 2022 Oct 5;13:961863. doi: 10.3389/fphar.2022.961863. eCollection 2022.
citation: Wang ZM, Chen XY, Bi J, Wang MY, Xu BP, Tang BH, Li C, Zhao W, Shen AD. Reappraisal of the Optimal Dose of Meropenem in Critically Ill Infants and Children: a Developmental Pharmacokinetic-Pharmacodynamic Analysis. Antimicrob Agents Chemother. 2020 Jul 22;64(8):e00760-20. doi: 10.1128/AAC.00760-20. Print 2020 Jul 22.