The effects of increased renal function on the blood concentration dynamics of antibiotic piperacillin/tazobactam

• Register: EUCTR
• Last refreshed on: 3 April 2017
• Main ID: EUCTR2016-003374-40-EE
• Date of registration: 24/10/2016
• Prospective Registration: Yes
• Primary sponsor: University of Tartu
• Public title: The effects of increased renal function on the blood concentration dynamics of antibiotic piperacillin/tazobactam
• Scientific title: The effects of augmented renal clearance on the pharmacokinetic/pharmacodynamic profile of piperacillin/tazobactam in children and young adults with malignant or non-malignant haematological or oncological diagnosis - The effect of augmented renal clearance on the pharmacokinetics of piperacillin/tazobactam
• Date of first enrolment: 29/11/2016
• Target sample size: 56
• Recruitment status: Authorised-recruitment may be ongoing or finished
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2016-003374-40
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: no Randomised: no Open: yes Single blind: no Double blind: no Parallel group: no Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: no Placebo: no Other: no
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): no Therapeutic confirmatory - (Phase III): no Therapeutic use (Phase IV): yes

Countries of recruitment

Estonia

Contacts

• Name: Department of Pharmacology
• Affiliation: University of Tartu

• Name: Department of Pharmacology
• Affiliation: University of Tartu

Key inclusion & exclusion criteria

Inclusion criteria:
1. Malignant or non-malignant haematological or oncological diagnosis
2. Chemotherapy or immunosuppressive therapy administered within last 12 months
3. Age from 6 months to 25 years
4. Clinically indicated and ordinated treatment with piperacillin/tazobactam based on the discretion of treating physician
5. Central venous, venous or arterial catheter inserted on clinical indications
6. eGFRcr > 80 ml/min/1.73 m2
7. Informed consent, if minor obtained from parents or legitimate representative of the child

Are the trial subjects under 18? yes
Number of subjects for this age range: 49
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 7
F.1.3 Elderly (>=65 years) no
F.1.3.1 Number of subjects for this age range

Exclusion criteria:
1. History of allergic reactions to piperacillin/tazobactam, penicillin’s, or other ß-lactam antibiotics or iohexol
2. Thyreotoxicosis
3. Presence of external drain
4. Ascites or generalised oedema
5. Received chemotherapy or immunosuppressive therapy during the last 24 hours
6. Received iohexol during last 24 hours
7. Participation in any other clinical study of investigational drugs within 4 weeks



Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Therapeutic area: Body processes [G] - Physiological processes [G07]

The state of renal hyperfiltration during infection in children and young adults with malignant or non-malignant haematological or oncological diagnosis

Intervention(s)

Trade Name: PIPERACILLIN/TAZOBACTAM TEVA
Product Name: PIPERACILLIN/TAZOBACTAM TEVA
Pharmaceutical Form: Powder for solution for infusion

Primary Outcome(s)

Secondary Objective: 1) To describe renal function in the studied cohort assessed by mGFR (iohexol clearance) and eGFR
2) To investigate whether there is a correlation between PK/PD profile of piperacillin/tazobactam with renal function in children and young adults with malignant or non-malignant haematological or oncological diagnosis, infection and mGFRioh above 80 ml/min/1.73 m2
3) To identify/describe metabolomic biomarkers involved in the pathogenesis of ARC in the studied cohort
4) To elaborate GFR values based on iohexol clearance suggestive of ARC in the studied cohort using population PK and modelling
5) To describe the prevalence of augmented renal clearance in the studied cohort
6) To propose optimal dosing for piperacillin/tazobactam in the studied cohort using population PK and modelling
7) To assess free antibiotic concentrations above the minimum inhibitory concentration (MIC) of the pathogen at both 50% (50% f T>MIC) and 100% (100% f T>MIC) of the dosing interval

Primary end point(s): The PK of piperacillin/tazobactam in children and young adults with malignant or non-malignant haematological or oncological diagnosis, infection and mGFRioh in between 80 to 160 ml/min/1.73 m2 (group 1) and above 160 ml/min/1.73 m2 (group 2)

Main Objective: To describe the PK of piperacillin/tazobactam in children and young adults with malignant or non-malignant haematological or oncological diagnosis, infection and eGFR between 80-160 ml/min/1.73 m2 (Group 1) and
above 160 ml/min/1.73 m2 (Group 2)

Timepoint(s) of evaluation of this end point: A total of 6 blood samples will be collected:
1st–immediately before the start of piperacillin/tazobactam infusion (study dose; baseline for iohexol and piperacillin/tazobactam)
2nd–30 min after the start of study dose infusion (Cmax for piperacillin/tazobactam together with iohexol administration)
3rd–35 min starting from study dose infusion (Cmax for iohexol)
4th–1h starting from study dose infusion (piperacillin/tazobactam 1h sample, iohexol 35 min sample)
5th–3,5h starting from study dose infusion (piperacillin/tazobactam 3,5h sample, iohexol 3h sample) + 1 additional sample for B2MG and CysC + 1 additional sample for metabolomic profiling
6th–6/8h starting from study dose infusion (piperacillin/tazobactam 6h/8h sample, iohexol 6h/8h sample)
5 urine samples will be collected.

Secondary Outcome(s)

Secondary end point(s): 1. The PK/PD profile (time over MIC) of piperacillin/tazobactam in children and young adults with malignant or non-malignant haematological or oncological diagnosis, infection and mGFRioh in between 80 to 160 ml/min/1.73 m2 (group 1) and above 160 ml/min/1.73 m2 (group 2)
2. The feasibility of iohexol clearance measurement to assess renal function in children and young adults with malignant or non-malignant haematological or oncological diagnosis, infection and eGFRcr in between 80 to 160 ml/min/1.73 m2 and above 160 ml/min/1.73 m2
3. Measurement of endogenous markers of renal function (creatinine, Cystatin C, NGAL, KIM-1, Il-18 beta2-microglobulin, uric acid, beta trace protein (BTP)) in children and young adults with malignant or non-malignant haematological or oncological diagnosis, infection and mGFRioh in between 80 to 160 ml/min/1.73 m2 (group 1) and above 160 ml/min/1.73 m2 (group 2)
4. Identification of metabolomic biomarkers involved in the pathogenesis of ARC in children and young adults with malignant or non-malignant haematological or oncological diagnosis and infection
5. Correlation of mGFRioh and calculated (using different equations) GFR values in children and young adults with malignant or non-malignant haematological or oncological diagnosis, infection and mGFRioh in between 80 to 160 ml/min/1.73 m2 (group 1) and above 160 ml/min/1.73 m2 (group 2)
6. Efficacy measures
a) clinical improvement at 72h after initiation of treatment and/or after study dose administration (whichever appropriate) defined as no need to change antibiotic therapy
b) elimination of the pathogen from the site of isolation at end of treatment (EOT) or on admission to home
c) significant improvement of baseline and thereafter daily collected laboratory parameters at end of treatment (EOT) or on admission to home

Timepoint(s) of evaluation of this end point: A total of 6 blood samples will be collected:
1st–immediately before the start of piperacillin/tazobactam infusion (study dose; baseline for iohexol and piperacillin/tazobactam)
2nd–30 min after the start of study dose infusion (Cmax for piperacillin/tazobactam)
3rd–35 min starting from study dose infusion (Cmax for iohexol)
4th–1h starting from study dose infusion
5th–3,5h starting from study dose infusion + 1 additional sample for B2MG and CysC + 1 additional sample for metabolomic profiling
6th–6/8h starting from study dose infusion
5 urine samples will be collected.
Laboratory and clinical parameters collected up to 6 days after the Study Dose administration

Secondary ID(s)

1-2016

Source(s) of Monetary Support

Estonian Research Council