Population Modeling of Anti-infective DrugsNCT05426499
Translational PKPD Modeling of Anti-infective Drugs Used in Pediatric Units.
An observational study of Population Modeling of Anti-infective Drugs, run by Poznan University of Medical Sciences at 4 sites in Poland.
Trial 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. Read more about this study
- Who is it for?
- Any age
- Conditions the study is for
- Population Modeling of Anti-infective Drugs
- What is being tested?
- Patients requiring cefotaxime treatment, Patients requiring meropenem treatment and Patients requiring fluconazole treatment
- How many people
- 150 participants
- Where
- 4 sitesPoland
- Study dates
- 1 Oct 2021to 30 Sep 2025
- Phase
- Observational
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages Any age
- All sexes
- No healthy volunteers
- Child, Adult, Older adult
Study population: The patients with bacterial and/or fungal infections demanding treatment by cefotaxime, meropenem, fluconazole, isavuconazole, or anidulafungin.
Who may be able to join
- 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.
Who cannot join
- 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
Trial locations and contacts
4 sites in 1 country.
Poland4 sites, 3 recruiting
- Recruiting
Szpital Kliniczny im. Karola Jonschera Uniwersytetu Medycznego im. Karola Marcinkowskiego w Poznaniu
Poznan, Greater Poland Voivodeship, 60-572
Alicja Bartkowska-Śniatkowska, MD, PhD, +48605558292, asniatko@ump.edu.pl
- Active, not recruiting
Poznan University of Medical Sciences, Department of Clinical Pharmacy and Biopharmacy
Poznan, Greater Poland Voivodeship, 60-806
- Not yet recruiting
Szpital Kliniczny im. Heliodora Święcickiego UMP
Poznan, Greater Poland Voivodeship, 61-848
Paweł Sobczyński, MD, PhD, psobczynski@ump.edu.pl
- Not yet recruiting
Wielkopolskie Centrum Onkologii
Poznan, Greater Poland Voivodeship, 61-866
Krzysztof Bieda, MD, PhD, krzysztof.bieda@wco.pl
About this study
Official title: 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.
Read the 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.
- Being tested
- Patients requiring cefotaxime treatment, Patients requiring meropenem treatment, Patients requiring fluconazole treatment, Patients requiring isavuconazole treatment, Patients requiring anidulafungin treatment
- Keywords
- Population modeling, Pediatric Units, Pharmacokinetics, Pharmacodynamics, Anti-infective drugs, Cefotaxime, Meropeneme, Fluconazole, Isavuconazole, Anidulafingin
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Patients requiring cefotaxime treatmentDrug
Dosage according to SmPC
Patients requiring meropenem treatmentDrug
Dosage according to SmPC
Patients requiring fluconazole treatmentDrug
Dosage according to SmPC
Patients requiring isavuconazole treatmentDrug
Dosage according to SmPC
Patients requiring anidulafungin treatmentDrug
Dosage according to SmPC
| Study group | Role | What they receive |
|---|---|---|
| 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. Receives: Drug: Patients requiring cefotaxime treatment | |
| 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. Receives: Drug: Patients requiring meropenem treatment | |
| 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. Receives: Drug: Patients requiring fluconazole treatment | |
| 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. Receives: Drug: Patients requiring isavuconazole treatment | |
| 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. Receives: Drug: Patients requiring anidulafungin treatment |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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 outcomes (10)
Minimum inhibitory concentration
The lowest concentration (in μg/mL) of an antibiotic that inhibits the growth of a given strain of bacteria.
Measured: On the first day after patient inclusion.
Plasma creatinine concentration
Measurement of creatinine concentrations in blood and urine.
Measured: On the first and sixth day after patient inclusion.
Creatinine clearance (CrCl)
Calculation of creatinine clearance (CrCl) based on measurement of creatinine concentration.
Measured: On the first and sixth day after patient inclusion.
Estimated GFR (eGFR)
Calculation of estimated GFR (eGFR) based on measurement of creatinine concentration.
Measured: On the first and sixth day after patient inclusion.
Bilirubin concentration
Measurement of bilirubin concentration
Measured: On the first and sixth day after patient inclusion.
Albumin concentration
Measurement of albumin concentration
Measured: On the first and sixth day after patient inclusion.
AST concentration
Measurement of AST concentration
Measured: On the first and sixth day after patient inclusion.
ALT concentration
Measurement of ALT concentration
Measured: On the first and sixth day after patient inclusion.
GGT concentration
Measurement of GGT concentration
Measured: On the first and sixth day after patient inclusion.
ALP concentration
Measurement of ALP concentration
Measured: On the first and sixth day after patient inclusion.
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted22 Jun 2022
- Study start1 Oct 2021
- Primary completion30 Jun 2025 (estimated)
- Study completion30 Sep 2025 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Population Modeling of Anti-infective DrugsStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Observational
- Observational model
- Cohort
- Time perspective
- Prospective
- Enrolment
- 150 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Poznan University of Medical Sciences
- Sponsor type
- University, hospital or other
- Collaborators
- University at Buffalo, The Greater Poland Cancer Centre
- Responsible party
- Principal investigator, Agnieszka Bienert, Poznan University of Medical Sciences
- Investigators
- Agnieszka Bienert, MSC,PhD, Principal investigator, Poznań University of Medical SciencesAlicja Bartkowska-Śniatkowska, MD, PhD, Principal investigator, Poznań University of Medical SciencesEdmund Grześkowiak, MSC, PhD, Study director, Poznań University of Medical SciencesWilliam J. Jusko, PhD, Study chair, School of Pharmacy and Pharmaceutical Sciences, Department of Pharmaceutical Sciences
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT05426499
- Sponsor's protocol ID
- 820/21
- Status last verified
- Jun 2024
- First submitted
- 17 Dec 2021
- Last updated
- 31 May 2025
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Yes: Pharmacokinetic and pharmacodynamic data (concentration/effect/time profiles) or individuals will be availabla
Study at a glance
From the registry record, last updated by the sponsor on 31 May 2025. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Translational PKPD Modeling of Anti-infective Drugs in Children Treated in Pediatric Units on the Example of Selected Antibiotics and Antifungals.
- ClinicalTrials.gov ID
- NCT05426499
- Acronym / sponsor ID
- 820/21
- Keywords
- Population modeling, Pediatric Units, Pharmacokinetics, Pharmacodynamics, Anti-infective drugs, Cefotaxime, Meropeneme, Fluconazole
- Study type
- Observational
- Recruitment status
- Unknown status
- Enrolment
- 150 participants (estimated)
- Lead sponsor
- Poznan University of Medical SciencesUniversity, hospital or other
- Collaborators
- University at Buffalo, The Greater Poland Cancer Centre
- Study start
- 1 Oct 2021 (actual)
- Primary completion
- 30 Jun 2025 (estimated)
- Study completion
- 30 Sep 2025 (estimated)
- First posted
- 22 Jun 2022 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
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
- Observational model
- Cohort
- Time perspective
- Prospective
- Number of arms
- 5
| Arm | Type | Receives |
|---|---|---|
| Patients requiring cefotaxime treatment | – | Drug: Patients requiring cefotaxime treatmentThe treatment choice and the recommended dosage will depend on the isolated pathogen. Therapy will be based on the SmPC of the appropriate drug. |
| Patients requiring meropenem treatment | – | Drug: Patients requiring meropenem treatmentThe treatment choice and the recommended dosage will depend on the isolated pathogen. Therapy will be based on the SmPC of the appropriate drug. |
| Patients requiring fluconazole treatment | – | Drug: Patients requiring fluconazole treatmentThe treatment choice and the recommended dosage will depend on the isolated pathogen. Therapy will be based on the SmPC of the appropriate drug. |
| Patients requiring isavuconazole treatment | – | Drug: Patients requiring isavuconazole treatmentThe treatment choice and the recommended dosage will depend on the isolated pathogen. Therapy will be based on the SmPC of the appropriate drug. |
| Patients requiring anidulafungin treatment | – | Drug: Patients requiring anidulafungin treatmentThe treatment choice and the recommended dosage will depend on the isolated pathogen. Therapy will be based on the SmPC of the appropriate drug. |
Who may qualify
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult, Older adult
- Study population
- The patients with bacterial and/or fungal infections demanding treatment by cefotaxime, meropenem, fluconazole, isavuconazole, or anidulafungin.
Key inclusion criteria (2 listed)
- 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.
Key exclusion criteria (4 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Patients requiring cefotaxime treatmentDosage according to SmPC | Drug | Patients requiring cefotaxime treatment |
| Patients requiring meropenem treatmentDosage according to SmPC | Drug | Patients requiring meropenem treatment |
| Patients requiring fluconazole treatmentDosage according to SmPC | Drug | Patients requiring fluconazole treatment |
| Patients requiring isavuconazole treatmentDosage according to SmPC | Drug | Patients requiring isavuconazole treatment |
| Patients requiring anidulafungin treatmentDosage according to SmPC | Drug | Patients requiring anidulafungin treatment |
Primary outcome
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.
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.
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.
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.
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.
10 secondary outcomes
Minimum inhibitory concentration
Time frame: On the first day after patient inclusion.
Plasma creatinine concentration
Time frame: On the first and sixth day after patient inclusion.
Creatinine clearance (CrCl)
Time frame: On the first and sixth day after patient inclusion.
Estimated GFR (eGFR)
Time frame: On the first and sixth day after patient inclusion.
Bilirubin concentration
Time frame: On the first and sixth day after patient inclusion.
Albumin concentration
Time frame: On the first and sixth day after patient inclusion.
AST concentration
Time frame: On the first and sixth day after patient inclusion.
ALT concentration
Time frame: On the first and sixth day after patient inclusion.
GGT concentration
Time frame: On the first and sixth day after patient inclusion.
ALP concentration
Time frame: On the first and sixth day after patient inclusion.
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 31 May 2025.
- Individual participant dataSharing planned: Yes. Pharmacokinetic and pharmacodynamic data (concentration/effect/time profiles) or individuals will be availabla
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Agnieszka Bienert, MSC,PhD principal investigator
Poznań University of Medical Sciences
Alicja Bartkowska-Śniatkowska, MD, PhD principal investigator
Poznań University of Medical Sciences
Edmund Grześkowiak, MSC, PhD study director
Poznań University of Medical Sciences
4 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of Population Modeling of Anti-infective Drugs, run by Poznan University of Medical Sciences at 4 sites in Poland.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 2 inclusion and 4 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: status not confirmed, as of the sponsor's last update on 31 May 2025. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 4 sites in Poland. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
Contact Agnieszka Bienert, MSC, PhD (+48616687844, agbienert@op.pl), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
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). The study lists 5 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 31 May 2025.