Translational PKPD Modeling of Anti-infective Drugs Used in Pediatric Units.
Study Details
Study Description
Brief Summary
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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
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 Design
Arms and Interventions
| Arm | 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. |
Drug: Patients requiring cefotaxime treatment
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. |
Drug: Patients requiring meropenem treatment
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. |
Drug: Patients requiring fluconazole treatment
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. |
Drug: Patients requiring isavuconazole treatment
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. |
Drug: Patients requiring anidulafungin treatment
Dosage according to SmPC
|
Outcome Measures
Primary Outcome Measures
- Cefotaxime plasma concentration [ng/ml] [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.
- Meropenem plasma concentration [ng/ml] [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.
- Fluconazole plasma concentration [ng/ml] [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.
- Isavuconazole plasma concentration [ng/ml] [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.
- Anidulafungin plasma concentration [ng/ml] [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.
Secondary Outcome Measures
- Minimum inhibitory concentration [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.
- Plasma creatinine concentration [On the first and sixth day after patient inclusion.]
Measurement of creatinine concentrations in blood and urine.
- Creatinine clearance (CrCl) [On the first and sixth day after patient inclusion.]
Calculation of creatinine clearance (CrCl) based on measurement of creatinine concentration.
- Estimated GFR (eGFR) [On the first and sixth day after patient inclusion.]
Calculation of estimated GFR (eGFR) based on measurement of creatinine concentration.
- Bilirubin concentration [On the first and sixth day after patient inclusion.]
Measurement of bilirubin concentration
- Albumin concentration [On the first and sixth day after patient inclusion.]
Measurement of albumin concentration
- AST concentration [On the first and sixth day after patient inclusion.]
Measurement of AST concentration
- ALT concentration [On the first and sixth day after patient inclusion.]
Measurement of ALT concentration
- GGT concentration [On the first and sixth day after patient inclusion.]
Measurement of GGT concentration
- ALP concentration [On the first and sixth day after patient inclusion.]
Measurement of ALP concentration
Eligibility Criteria
Criteria
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
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Szpital Kliniczny im. Heliodora Święcickiego UMP | Poznań | Długa 1/2 | Poland | 61-848 |
| 2 | Wielkopolskie Centrum Onkologii | Poznań | Garbary 15 | Poland | 61-866 |
| 3 | Poznan University of Medical Sciences, Department of Clinical Pharmacy and Biopharmacy | Poznań | Rokietnicka 7 | Poland | 60-806 |
| 4 | Szpital Kliniczny im. Karola Jonschera Uniwersytetu Medycznego im. Karola Marcinkowskiego w Poznaniu | Poznań | Szpitalna 27/33 | Poland | 60-572 |
Sponsors and Collaborators
- Poznan University of Medical Sciences
- University at Buffalo
- The Greater Poland Cancer Centre
Investigators
- Principal Investigator: Agnieszka Bienert, MSC,PhD, Poznań University of Medical Sciences
- Principal Investigator: Alicja Bartkowska-Śniatkowska, MD, PhD, Poznań University of Medical Sciences
- Study Director: Edmund Grześkowiak, MSC, PhD, Poznań University of Medical Sciences
- Study Chair: William J. Jusko, PhD, School of Pharmacy and Pharmaceutical Sciences, Department of Pharmaceutical Sciences
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- 820/21