Translational PKPD Modeling of Anti-infective Drugs Used in Pediatric Units.

June 21, 2022 updated by: Agnieszka Bienert, Poznan University of Medical Sciences

Translational PKPD Modeling of Anti-infective Drugs in Children Treated in Pediatric Units on the Example of Selected Antibiotics and Antifungals.

Pharmacokinetic and pharmacodynamic modeling (PKPD) is becoming an essential tool for optimizing pharmacotherapy. Building mechanistic models allows determining the relationship between the dose, concentration, pharmacological effect, and side effects in various populations. The growing resistance to drugs among bacteria is a challenge for medicine, and the progress in pharmacometrics enables us to make rational clinical decisions. A particular group of patients is children with differences in PK and PD of drugs. The lack of clinical studies often forces to extrapolate dosing based on the results obtained in adults. In intensive care units, up to 70-90% of drugs in children are used off-label. Drug agencies point to the importance of the population-based approach to data analysis, especially in infants and children. Under the project, work will focus on the PK and PD of antifungal drugs (fluconazole, isavuconazole, and anidulafungin) and antibiotics (cefotaxime and meropenem) in the pediatric and adult populations. The choice of topic is dictated by the growing need to create PKPD models of the drugs mentioned above in children. The hypothesis is the assumption that using a mathematical model will enable to describe the time course of the drug in the organism, the relationship between the effect and the dose of the medicine and its concentration in the plasma, and the influence of individual factors on the PKPD profile of a drug.

Study Overview

Detailed Description

Cefotaxime and meropenem are broad-spectrum antibiotics, most commonly prescribed in pediatric and adult intensive care units. Unfortunately, the applied dosing regimens based on the results obtained in adults or only on drug pharmacokinetics (without taking into account the pharmacodynamic profile) often fail. The situation is additionally complicated by the observed clinically significant drug interactions. The results of published studies indicate the need to develop PKPD models for these drugs in the pediatric and adult populations. Fluconazole, isavuconazole and anidulafungin are the azole anti-fungal drugs and echinocandin. Despite the optimistic results of studies in adults, showing high efficacy, a favorable PK profile, and the safety profile of these therapeutics, there are no studies in children.

The research will be conducted at the Pediatric Clinical Hospital of K. Jonscher, The Greater Poland Cancer Center, and Heliodor Święcicki Clinical Hospital of the Medical University in Poznań. With the approval of the Bioethics Committee, about 150 children and adults will be included in the study. Blood samples will be collected at appropriate time points to investigate the PK profile. The measured pharmacological effect will be the minimum inhibitory concentration (MIC). PKPD indices will be included in the model, depending on the tested drug: T> MIC, Cmax / MIC, and AUC / MIC. The values of covariates that may affect drug PK and PD will be reported. The analysis will consider the polymorphisms of the OAT3 organic anion transporter genes and the MRP4 transport protein. HPLC will examine plasma drug concentration levels in conjunction with UV detection. The Xevo TQ-S micro triple quadrupole mass spectrometer, coupled with ultra-efficient liquid chromatography with the PDA acquity UPLC detector I-class PDA Waters. The genetic polymorphism of selected genes will be tested by real-time PCR using the LightCycler® 480 II Instrument. The PKPD population analysis will be performed by nonlinear modeling of mixed-effects using NONMEM version 7.2.0, the GNU Fortran 9.0 compiler, and Wings for NONMEM and RStudio. The collected data will be used to build hypothetical models using neural networks.

The expected result of the project's primary goal is to build PKPD models of fluconazole, isavuconazole, anidulafungin, cefotaxime, and meropenem in the pediatric and adult populations. According to the final model's principles, they will be evaluated and can serve as a specialized tool for personalizing pharmacotherapy.

Study Type

Observational

Enrollment (Anticipated)

150

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

    • Długa 1/2
      • Poznań, Długa 1/2, Poland, 61-848
        • Szpital Kliniczny im. Heliodora Święcickiego UMP
    • Garbary 15
      • Poznań, Garbary 15, Poland, 61-866
        • Wielkopolskie Centrum Onkologii
    • Rokietnicka 7
      • Poznań, Rokietnicka 7, Poland, 60-806
        • Poznan University of Medical Sciences, Department of Clinical Pharmacy and Biopharmacy
    • Szpitalna 27/33
      • Poznań, Szpitalna 27/33, Poland, 60-572
        • Szpital Kliniczny im. Karola Jonschera Uniwersytetu Medycznego im. Karola Marcinkowskiego w Poznaniu

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • ADULT
  • OLDER_ADULT
  • CHILD

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Sampling Method

Probability Sample

Study Population

The patients with bacterial and/or fungal infections demanding treatment by cefotaxime, meropenem, fluconazole, isavuconazole, or anidulafungin.

Description

Inclusion Criteria:

  • Obtaining informed consent from the patient/parent of the patient
  • A bacterial and fungal infection that requires the use of at least one of the drugs listed based on clinical indications and the attending physician's decision.

Exclusion Criteria:

  • Proven allergic reaction to medications used
  • No written consent
  • Contraindications in SmPC
  • Combination therapy with at least two antibacterial drugs and/or at least two antifungal drugs

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

Cohorts and Interventions

Group / Cohort
Intervention / Treatment
Patients requiring cefotaxime treatment
The treatment choice and the recommended dosage will depend on the isolated pathogen. Therapy will be based on the SmPC of the appropriate drug.
Dosage according to SmPC
Patients requiring meropenem treatment
The treatment choice and the recommended dosage will depend on the isolated pathogen. Therapy will be based on the SmPC of the appropriate drug.
Dosage according to SmPC
Patients requiring fluconazole treatment
The treatment choice and the recommended dosage will depend on the isolated pathogen. Therapy will be based on the SmPC of the appropriate drug.
Dosage according to SmPC
Patients requiring isavuconazole treatment
The treatment choice and the recommended dosage will depend on the isolated pathogen. Therapy will be based on the SmPC of the appropriate drug.
Dosage according to SmPC
Patients requiring anidulafungin treatment
The treatment choice and the recommended dosage will depend on the isolated pathogen. Therapy will be based on the SmPC of the appropriate drug.
Dosage according to SmPC

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Cefotaxime plasma concentration [ng/ml]
Time Frame: Just before the next dose and at 0.33; 0.66; 1; 2; 4; 6; 8 hours after the start of drug administration
Measurements of cefotaxime plasma concentrations [ng/ml] before and after dosage of a drug. Blood samples were collected according to the study protocol.
Just before the next dose and at 0.33; 0.66; 1; 2; 4; 6; 8 hours after the start of drug administration
Meropenem plasma concentration [ng/ml]
Time Frame: Just before the next dose and at 1,5; 3; 6; 8 hours after the start of drug administration
Measurements of meropenem plasma concentrations [ng/ml] before and after dosage of a drug. Blood samples were collected according to the study protocol.
Just before the next dose and at 1,5; 3; 6; 8 hours after the start of drug administration
Fluconazole plasma concentration [ng/ml]
Time Frame: Just before the next dose and at 0,5; 1; 3; 10; 24 hours after the start of drug administration
Measurements of fluconazole plasma concentrations [ng/ml] before and after dosage of a drug. Blood samples were collected according to the study protocol.
Just before the next dose and at 0,5; 1; 3; 10; 24 hours after the start of drug administration
Isavuconazole plasma concentration [ng/ml]
Time Frame: Just before the next dose and at 0,25; 0,5; 0,75; 1; 1,25; 1,5; 2; 3; 4; 6; 8; 10; 12; 14; 16; 24 hours after the start of drug administration
Measurements of isavuconazole plasma concentrations [ng/ml] before and after dosage of a drug. Blood samples were collected according to the study protocol.
Just before the next dose and at 0,25; 0,5; 0,75; 1; 1,25; 1,5; 2; 3; 4; 6; 8; 10; 12; 14; 16; 24 hours after the start of drug administration
Anidulafungin plasma concentration [ng/ml]
Time Frame: Just before the next dose and at 0,5; 1; 1,5; 2; 4; 6; 8; 10; 12; 24 hours after the start of drug administration
Measurements of anidulafungin plasma concentrations [ng/ml] before and after dosage of a drug. Blood samples were collected according to the study protocol.
Just before the next dose and at 0,5; 1; 1,5; 2; 4; 6; 8; 10; 12; 24 hours after the start of drug administration

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Minimum inhibitory concentration
Time Frame: On the first day after patient inclusion.
The lowest concentration (in μg/mL) of an antibiotic that inhibits the growth of a given strain of bacteria.
On the first day after patient inclusion.
Plasma creatinine concentration
Time Frame: On the first and sixth day after patient inclusion.
Measurement of creatinine concentrations in blood and urine.
On the first and sixth day after patient inclusion.
Creatinine clearance (CrCl)
Time Frame: On the first and sixth day after patient inclusion.
Calculation of creatinine clearance (CrCl) based on measurement of creatinine concentration.
On the first and sixth day after patient inclusion.
Estimated GFR (eGFR)
Time Frame: On the first and sixth day after patient inclusion.
Calculation of estimated GFR (eGFR) based on measurement of creatinine concentration.
On the first and sixth day after patient inclusion.
Bilirubin concentration
Time Frame: On the first and sixth day after patient inclusion.
Measurement of bilirubin concentration
On the first and sixth day after patient inclusion.
Albumin concentration
Time Frame: On the first and sixth day after patient inclusion.
Measurement of albumin concentration
On the first and sixth day after patient inclusion.
AST concentration
Time Frame: On the first and sixth day after patient inclusion.
Measurement of AST concentration
On the first and sixth day after patient inclusion.
ALT concentration
Time Frame: On the first and sixth day after patient inclusion.
Measurement of ALT concentration
On the first and sixth day after patient inclusion.
GGT concentration
Time Frame: On the first and sixth day after patient inclusion.
Measurement of GGT concentration
On the first and sixth day after patient inclusion.
ALP concentration
Time Frame: On the first and sixth day after patient inclusion.
Measurement of ALP concentration
On the first and sixth day after patient inclusion.

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Investigators

  • Principal Investigator: Agnieszka Bienert, MSC,PhD, Poznan University of Medical Sciences
  • Principal Investigator: Alicja Bartkowska-Śniatkowska, MD, PhD, Poznan University of Medical Sciences
  • Study Chair: William J. Jusko, PhD, School of Pharmacy and Pharmaceutical Sciences, Department of Pharmaceutical Sciences

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (ACTUAL)

October 1, 2021

Primary Completion (ANTICIPATED)

June 30, 2023

Study Completion (ANTICIPATED)

September 30, 2025

Study Registration Dates

First Submitted

December 17, 2021

First Submitted That Met QC Criteria

June 21, 2022

First Posted (ACTUAL)

June 22, 2022

Study Record Updates

Last Update Posted (ACTUAL)

June 22, 2022

Last Update Submitted That Met QC Criteria

June 21, 2022

Last Verified

June 1, 2022

More Information

Terms related to this study

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

YES

IPD Plan Description

Pharmacokinetic and pharmacodynamic data (concentration/effect/time profiles) or individuals will be availabla

IPD Sharing Time Frame

The data will be available in 6-12 months and available for 5 years

IPD Sharing Access Criteria

Scientists

IPD Sharing Supporting Information Type

  • STUDY_PROTOCOL
  • SAP
  • ICF
  • CSR

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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