Systemic Infections
Conditions
Keywords
Ceftazidime, Avibactam, Anti-Infectives
Brief summary
To assess the pharmacokinetics, safety and tolerability of a single dose of CAZ-AVI in children from 3 months of age to \<18 years.
Detailed description
This is a phase I, open-label, single-dose study. The study aims to characterize the pharmacokinetics of CAZ-AVI and assess its safety and tolerability following a single IV dose given to hospitalized pediatric patients receiving systemic antibiotic therapy for suspected or confirmed infection. This study will include 4 cohorts, each consisting of at least 8 evaluable pediatric patients, aged ≥3 months to \<18 years, who are hospitalized with infections.
Interventions
DRUGCAZ-AVI
Single IV dose of Ceftazidime and Avibactam. Dosage regimen will vary depending on cohort.
Sponsors
Forest Laboratories
Pfizer
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
BASIC_SCIENCE
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
3 Months to 17 Years
Healthy volunteers
No
Inclusion criteria
1. Written informed consent will be obtained from parent(s) or other legally acceptable representative(s), and informed assent from patient (if age appropriate) will be obtained 2. Male or female children ages ≥3 months to \<18 years. 3. Hospitalized, receiving systemic antibiotic therapy for the treatment of a suspected or confirmed infection, and expected to require hospitalization until after the end of treatment (EOT) evaluations are completed. 4. If female and has reached menarche, or has reached Tanner stage 3 breast development (even if not having reached menarche), the patient is practicing appropriate birth control or is sexually abstinent. 5. Likely to survive the current illness or hospitalization. 6. Sufficient intravascular access (peripheral or central) to receive study drug.
Exclusion criteria
1. History of hypersensitivity reactions to carbapenems, cephalosporins, penicillin, other β-lactam antibiotics. 2. If female, currently pregnant or breast feeding or has a positive serum β-human chorionic gonadotropin (β-hCG) pregnancy test. 3. Receipt of a blood or blood component (e.g., red blood cells, fresh frozen plasma, platelets) transfusion during the 24-hour period before enrolment. 4. BMI outside the range (below the 5th percentile or above the 85th percentile) for height, age, and weight except for children \<2 years of age. 5. Babies born prior to 37 weeks gestation (cohort 4 only).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Pharmacokinetic Parameters of Avibactam and Ceftazidime for Cohort 1 and 2: AUC | Day 1 | Key PK parameters were prespecified to be calculated for cohorts 1 and 2. For cohorts 3 and 4 (where children were \<6 years of age), sparse sampling scheme was used for PK samples to limit the volume of blood required. PK parameters cannot be derived from these sparse PK samples without population PK analysis. Thus the PK is not described here, but will be reported in a separate population PK report. |
| Pharmacokinetic Parameters of Avibactam and Ceftazidime for Cohort 1 and 2: Cmax | Day 1 | Key PK parameters are shown for cohorts 1 and 2. For cohorts 3 and 4 (where children were \<6 years of age), sparse sampling scheme was used for PK samples to limit the volume of blood required. PK parameters cannot be derived from these sparse PK samples without population PK analysis. Thus the PK is not described here, but will be reported in a separate population PK report. |
Countries
United States
Participant flow
Recruitment details
First patient enrolled: 26 July 2013 Last patient last visit: 09 October 2014
Pre-assignment details
Eligibility was determined by investigator, prior to enrollment. Patients were selected on the basis of the age requirements for the appropriate cohort and after obtaining written informed consent from the parent or legal guardian and assent from patients (as appropriate). Screening assessments were completed prior to study drug administration.
Participants by arm
| Arm | Count |
|---|---|
| Cohort 1 aged ≥12 to \<18 years 2000 mg ceftazidime and 500 mg avibactam | 8 |
| Cohort 2 aged ≥6 to \<12 years Weight \<40 kg: 50 mg/kg ceftazidime and 12.5 mg/kg avibactam Weight ≥40 kg: 2000 mg ceftazidime and 500 mg avibactam | 8 |
| Cohort 3 aged ≥2 to \<6 years Normal renal function or mild renal insufficiency: 50 mg/kg ceftazidime and 12.5 mg/kg avibactam.
Moderate renal insufficiency: 25 mg/kg ceftazidime and 6.25 mg/kg avibactam | 8 |
| Cohort 4 aged ≥3 months to \<2 years Normal renal function or mild renal insufficiency: 50 mg/kg ceftazidime and 12.5 mg/kg avibactam.
Moderate renal insufficiency: 25 mg/kg ceftazidime and 6.25 mg/kg avibactam | 8 |
| Total | 32 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Lost to Follow-up | 0 | 1 | 0 | 0 |
| Overall Study | Protocol Violation | 1 | 0 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 2 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Cohort 1 | Cohort 2 | Cohort 3 | Cohort 4 | Total |
|---|---|---|---|---|---|
| Age, Continuous | 14.945 years STANDARD_DEVIATION 1.5599 | 8.020 years STANDARD_DEVIATION 1.4036 | 3.519 years STANDARD_DEVIATION 1.0044 | 0.924 years STANDARD_DEVIATION 0.5007 | 6.852 years STANDARD_DEVIATION 5.52 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 1 Participants | 3 Participants | 1 Participants | 5 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 8 Participants | 7 Participants | 5 Participants | 7 Participants | 27 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 2 Participants | 0 Participants | 3 Participants | 6 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 6 Participants | 6 Participants | 7 Participants | 5 Participants | 24 Participants |
| Sex: Female, Male Female | 5 Participants | 3 Participants | 6 Participants | 3 Participants | 17 Participants |
| Sex: Female, Male Male | 3 Participants | 5 Participants | 2 Participants | 5 Participants | 15 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 0 / 8 | 0 / 8 | 4 / 8 | 2 / 8 |
| serious Total, serious adverse events | 0 / 8 | 0 / 8 | 0 / 8 | 0 / 8 |
Outcome results
Primary
Pharmacokinetic Parameters of Avibactam and Ceftazidime for Cohort 1 and 2: AUC
Key PK parameters were prespecified to be calculated for cohorts 1 and 2. For cohorts 3 and 4 (where children were \<6 years of age), sparse sampling scheme was used for PK samples to limit the volume of blood required. PK parameters cannot be derived from these sparse PK samples without population PK analysis. Thus the PK is not described here, but will be reported in a separate population PK report.
Time frame: Day 1
Population: Pharmacokinetic analysis set
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1 / Avibactam | Pharmacokinetic Parameters of Avibactam and Ceftazidime for Cohort 1 and 2: AUC | AUC(0-8) | 35140 h*ng/mL | Geometric Coefficient of Variation 33.11 |
| Cohort 1 / Avibactam | Pharmacokinetic Parameters of Avibactam and Ceftazidime for Cohort 1 and 2: AUC | AUC(0-inf) | 36430 h*ng/mL | Geometric Coefficient of Variation 33.61 |
| Cohort 1 / Avibactam | Pharmacokinetic Parameters of Avibactam and Ceftazidime for Cohort 1 and 2: AUC | AUC(0-t) | 36250 h*ng/mL | Geometric Coefficient of Variation 33.7 |
| Cohort 1 / Ceftazidime | Pharmacokinetic Parameters of Avibactam and Ceftazidime for Cohort 1 and 2: AUC | AUC(0-8) | 219100 h*ng/mL | Geometric Coefficient of Variation 29.69 |
| Cohort 1 / Ceftazidime | Pharmacokinetic Parameters of Avibactam and Ceftazidime for Cohort 1 and 2: AUC | AUC(0-inf) | 230600 h*ng/mL | Geometric Coefficient of Variation 30.7 |
| Cohort 1 / Ceftazidime | Pharmacokinetic Parameters of Avibactam and Ceftazidime for Cohort 1 and 2: AUC | AUC(0-t) | 229200 h*ng/mL | Geometric Coefficient of Variation 30.86 |
| Cohort 2 / Avibactam | Pharmacokinetic Parameters of Avibactam and Ceftazidime for Cohort 1 and 2: AUC | AUC(0-t) | 34380 h*ng/mL | Geometric Coefficient of Variation 23.37 |
| Cohort 2 / Avibactam | Pharmacokinetic Parameters of Avibactam and Ceftazidime for Cohort 1 and 2: AUC | AUC(0-8) | 33590 h*ng/mL | Geometric Coefficient of Variation 22.15 |
| Cohort 2 / Avibactam | Pharmacokinetic Parameters of Avibactam and Ceftazidime for Cohort 1 and 2: AUC | AUC(0-inf) | 34820 h*ng/mL | Geometric Coefficient of Variation 22.62 |
| Cohort 2 / Ceftazidime | Pharmacokinetic Parameters of Avibactam and Ceftazidime for Cohort 1 and 2: AUC | AUC(0-8) | 212400 h*ng/mL | Geometric Coefficient of Variation 16.28 |
| Cohort 2 / Ceftazidime | Pharmacokinetic Parameters of Avibactam and Ceftazidime for Cohort 1 and 2: AUC | AUC(0-inf) | 221200 h*ng/mL | Geometric Coefficient of Variation 17.38 |
| Cohort 2 / Ceftazidime | Pharmacokinetic Parameters of Avibactam and Ceftazidime for Cohort 1 and 2: AUC | AUC(0-t) | 217800 h*ng/mL | Geometric Coefficient of Variation 18.36 |
Primary
Pharmacokinetic Parameters of Avibactam and Ceftazidime for Cohort 1 and 2: Cmax
Key PK parameters are shown for cohorts 1 and 2. For cohorts 3 and 4 (where children were \<6 years of age), sparse sampling scheme was used for PK samples to limit the volume of blood required. PK parameters cannot be derived from these sparse PK samples without population PK analysis. Thus the PK is not described here, but will be reported in a separate population PK report.
Time frame: Day 1
Population: Pharmacokinetic analysis set
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1 / Avibactam | Pharmacokinetic Parameters of Avibactam and Ceftazidime for Cohort 1 and 2: Cmax | 15090 ng/mL | Geometric Coefficient of Variation 52.42 |
| Cohort 1 / Ceftazidime | Pharmacokinetic Parameters of Avibactam and Ceftazidime for Cohort 1 and 2: Cmax | 79750 ng/mL | Geometric Coefficient of Variation 41.81 |
| Cohort 2 / Avibactam | Pharmacokinetic Parameters of Avibactam and Ceftazidime for Cohort 1 and 2: Cmax | 14140 ng/mL | Geometric Coefficient of Variation 22.96 |
| Cohort 2 / Ceftazidime | Pharmacokinetic Parameters of Avibactam and Ceftazidime for Cohort 1 and 2: Cmax | 81270 ng/mL | Geometric Coefficient of Variation 17.81 |