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| Name | Class |
|---|---|
| University at Buffalo | OTHER |
| The Greater Poland Cancer Centre | OTHER |
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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| 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. |
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| 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. |
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| 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. |
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| 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. |
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| 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. |
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Patients requiring cefotaxime treatment | Drug | Dosage according to SmPC |
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| Measure | Description | Time Frame |
|---|---|---|
| Cefotaxime plasma concentration [ng/ml] | 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] | 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] | 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] | 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] | 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 |
| Measure | Description | Time Frame |
|---|---|---|
| Minimum inhibitory concentration | 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 |
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Inclusion Criteria:
Exclusion Criteria:
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The patients with bacterial and/or fungal infections demanding treatment by cefotaxime, meropenem, fluconazole, isavuconazole, or anidulafungin.
| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Agnieszka Bienert, MSC, PhD | Contact | +48616687844 | agbienert@op.pl | |
| Arkadiusz Adamiszak, MSC | Contact | +48536551662 | arkadiusz.adamiszak@gmail.com |
| Name | Affiliation | Role |
|---|---|---|
| Agnieszka Bienert, MSC,PhD | Poznań University of Medical Sciences | Principal Investigator |
| Alicja Bartkowska-Śniatkowska, MD, PhD | Poznań University of Medical Sciences | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Szpital Kliniczny im. Karola Jonschera Uniwersytetu Medycznego im. Karola Marcinkowskiego w Poznaniu | Recruiting | Poznan | Greater Poland Voivodeship | 60-572 | Poland |
Pharmacokinetic and pharmacodynamic data (concentration/effect/time profiles) or individuals will be availabla
The data will be available in 6-12 months and available for 5 years
Scientists
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| Patients requiring meropenem treatment | Drug | Dosage according to SmPC |
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| Patients requiring fluconazole treatment | Drug | Dosage according to SmPC |
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| Patients requiring isavuconazole treatment | Drug | Dosage according to SmPC |
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| Patients requiring anidulafungin treatment | Drug | Dosage according to SmPC |
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Measurement of creatinine concentrations in blood and urine.
| On the first and sixth day after patient inclusion. |
| Creatinine clearance (CrCl) | Calculation of creatinine clearance (CrCl) based on measurement of creatinine concentration. | On the first and sixth day after patient inclusion. |
| Estimated GFR (eGFR) | Calculation of estimated GFR (eGFR) based on measurement of creatinine concentration. | On the first and sixth day after patient inclusion. |
| Bilirubin concentration | Measurement of bilirubin concentration | On the first and sixth day after patient inclusion. |
| Albumin concentration | Measurement of albumin concentration | On the first and sixth day after patient inclusion. |
| AST concentration | Measurement of AST concentration | On the first and sixth day after patient inclusion. |
| ALT concentration | Measurement of ALT concentration | On the first and sixth day after patient inclusion. |
| GGT concentration | Measurement of GGT concentration | On the first and sixth day after patient inclusion. |
| ALP concentration | Measurement of ALP concentration | On the first and sixth day after patient inclusion. |
| Edmund Grześkowiak, MSC, PhD | Poznań University of Medical Sciences | Study Director |
| William J. Jusko, PhD | School of Pharmacy and Pharmaceutical Sciences, Department of Pharmaceutical Sciences | Study Chair |
| Poznan University of Medical Sciences, Department of Clinical Pharmacy and Biopharmacy | Active, not recruiting | Poznan | Greater Poland Voivodeship | 60-806 | Poland |
| Szpital Kliniczny im. Heliodora Święcickiego UMP | Not yet recruiting | Poznan | Greater Poland Voivodeship | 61-848 | Poland |
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| Wielkopolskie Centrum Onkologii | Not yet recruiting | Poznan | Greater Poland Voivodeship | 61-866 | Poland |
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