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Clinical Therapeutics

Phase I Study Assessing the Pharmacokinetic Profile, Safety, and Tolerability of a Single Dose of Ceftazidime-Avibactam in Hospitalized Pediatric Patients

John S. Bradley, Jon Armstrong, Antonio Arrieta, Raafat Bishai, Shampa Das, Shirley Delair, Timi Edeki, William C. Holmes, Jianguo Li, Kathryn S. Moffett, Deepa Mukundan, Norma Perez, José R. Romero, David Speicher, Janice E. Sullivan, Diansong Zhou
John S. Bradley
aUniversity of California, San Diego, California, USA
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Jon Armstrong
bAstraZeneca, Macclesfield, United Kingdom
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Antonio Arrieta
cChildren's Hospital of Orange County, Orange, California, USA
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Raafat Bishai
dAstraZeneca, Gaithersburg, Maryland, USA
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Shampa Das
bAstraZeneca, Macclesfield, United Kingdom
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Shirley Delair
eChildren's Hospital & Medical Center, Omaha, Nebraska, USA
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Timi Edeki
fAstraZeneca, Wilmington, Delaware, USA
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William C. Holmes
dAstraZeneca, Gaithersburg, Maryland, USA
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Jianguo Li
gAstraZeneca, Waltham, Massachusetts, USA
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Kathryn S. Moffett
hWest Virginia University, Morgantown, West Virginia, USA
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Deepa Mukundan
iUniversity of Toledo, Toledo, Ohio, USA
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Norma Perez
jUniversity of Texas Health Science Center, Houston, Texas, USA
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José R. Romero
kUniversity of Arkansas for Medical Sciences and Arkansas Children's Hospital, Little Rock, Arkansas, USA
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David Speicher
lUniversity Hospitals Rainbow Babies and Children's Hospital, Cleveland, Ohio, USA
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Janice E. Sullivan
mUniversity of Louisville and Kosair Children's Hospital, Louisville, Kentucky, USA
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Diansong Zhou
gAstraZeneca, Waltham, Massachusetts, USA
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DOI: 10.1128/AAC.00862-16
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  • FIG 1
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    FIG 1

    Arithmetic mean (±SD) plasma concentration-time curves for ceftazidime for cohorts 1 to 4 following single-dose (day 1) administration of ceftazidime-avibactam (pharmacokinetic analysis population).

  • FIG 2
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    FIG 2

    Arithmetic mean (±SD) plasma concentration-time curves for avibactam for cohorts 1 to 4 following single-dose (day 1) administration of ceftazidime-avibactam (pharmacokinetic analysis population).

Tables

  • Figures
  • TABLE 1

    Summary of dose regimen used in the study

    DrugDose (all administered as a 2-h i.v. infusion) for cohort:
    1 (≥12 yr to <18 yr)2 (≥6 yr to <12 yr)3 (≥2 yr to <6 yr)4 (≥3 mo to <2 yr)
    ≥40 kg<40 kg
    Ceftazidime2,000 mg2,000 mg50 mg/kg50 mg/kg50 mg/kg
    Avibactam500 mg500 mg12.5 mg/kg12.5 mg/kg12.5 mg/kg
  • TABLE 2

    Baseline patient characteristics (safety analysis population)

    ParameterValue for cohort:
    1 (≥12 to <18 yr) (n = 8)2 (≥6 to <12 yr) (n = 8)3 (≥2 to <6 yr) (n = 8)4 (≥3 mo to <2 yr) (n = 8)
    Age, yr
        Mean (SD)14.9 (1.6)8.0 (1.4)3.5 (1.0)0.9 (0.5)
        Median (range)14.9 (13.0–17.3)7.7 (6.5–10.8)3.8 (2.1–4.9)0.9 (0.3–1.8)
    Female, n (%)5 (62.5)3 (37.5)6 (75.0)3 (37.5)
    Race, n (%)
        White6 (75.0)6 (75.0)7 (87.5)5 (62.5)
        Black or African American1 (12.5)2 (25.0)03 (37.5)
        Othera1 (12.5)01 (12.5)0
    Weight, kg; mean (SD)51.90 (7.15)24.95 (3.03)15.73 (2.39)9.20 (2.51)
    BMI, kg/m2; mean (SD)20.80 (3.21)15.41 (0.78)15.47 (0.95)NAd
    CrCL, ml/min/1.73 m2; mean (SD)115.29 (18.14)156.97b (42.92)181.57 (100.99)104.35 (26.20)
    Normal renal function, n (%)8 (100)8 (100)8 (100)8 (100)
    Any concomitant antibiotic,c n (%)8 (100)8 (100)8 (100)8 (100)
        Lincosamides3 (37.5)2 (25.0)4 (50.0)6 (75.0)
        3rd-generation cephalosporins other than ceftazidime1 (12.5)3 (37.5)1 (12.5)1 (12.5)
        Penicillins plus β-lactamase inhibitors1 (12.5)02 (25.0)2 (25.0)
        Vancomycin1 (12.5)1 (12.5)02 (25.0)
        Metronidazole2 (25.0)2 (25.0)00
        Aminoglycosides2 (25.0)1 (12.5)01 (12.5)
        1st-generation cephalosporins1 (12.5)01 (12.5)1 (12.5)
        Azithromycin1 (12.5)1 (12.5)1 (12.5)0
        Extended-spectrum penicillin1 (12.5)1 (12.5)1 (12.5)0
        Meropenem02 (25.0)00
        Levofloxacin002 (25.0)0
    • ↵a Asian (n = 1 in cohort 3 [≥2 to <6 years]) and American Indian or Alaskan native (n = 1 in cohort 1 [≥12 to <18 years]).

    • ↵b One patient in cohort 2 (≥6 to <12 years) had a value greater than the upper limit of normal and is not included in the mean (SD) calculation.

    • ↵c Taken any time between the initiation of study therapy and the day 3 follow-up assessment. Most commonly used antibiotics/groups are shown.

    • ↵d NA, not applicable.

  • TABLE 3

    Summary of ceftazidime and avibactam pharmacokinetic parameters measured in pediatric patients (pharmacokinetic population)

    Drug and parameteraValue for cohort:
    1 (n = 8) (≥12 to <18 yr)2 (n = 8) (≥6 to <12 yr)3 (n = 8) (≥2 to <6 yr)4 (n = 8) (≥3 mo to <2 yr)
    Ceftazidime
        Cmax (mg/liter)79.8 (41.8)81.3 (17.8)80.1b (14.7)91.7b (19.6)
        tmaxc (h)2.0 (1.9–2.6)2.1 (1.9–2.4)
        AUC0–t (h · mg/liter)229.2 (30.9)217.8 (18.4)
        AUC0–∞ (h · mg/liter)230.6 (30.7)221.2 (17.4)
        t1/2c (h)1.7 (0.9–2.8)1.6 (0.9–1.8)
        Vss (liters)22.2 (42.0)13.0 (17.8)
        CL (liter/h)8.7 (45.5)5.6 (16.0)
        CL/W (liter/kg/h)0.169 (37.9)0.226 (20.0)
    Avibactam
        Cmax (mg/liter)15.1 (52.4)14.1 (23.0)13.7b (22.4)16.3b (22.6)
        tmax (h)2.0 (1.9–2.6)2.1 (1.9–2.4)
        AUC0–t (h · mg/liter)36.3 (33.7)34.4 (23.4)
        AUC0–∞ (h · mg/liter)36.4 (33.6)34.8 (22.6)
        t1/2 (h)1.6 (0.9–2.8)1.7 (0.9–2.0)
        Vss (liters)31.0 (53.3)19.3 (27.0)
        CL (liter/h)13.7 (52.6)8.9 (30.2)
        CL/W (liter/kg/h)0.267 (44.2)0.359 (35.8)
    • ↵a Values are geometric mean (coefficient of variation [%]) unless stated otherwise. CL/W, weighted clearance or clearance by body weight.

    • ↵b Plasma concentration as measured at end of infusion.

    • ↵c Median (range).

  • TABLE 4

    Summary of ceftazidime and avibactam observed and population pharmacokinetic model-predicted exposures in pediatric patients (pharmacokinetic population)

    DrugAUC0-∞ (h · mg/liter)
    Observed value for cohorta:Predicted value for cohortb:Value for adult reference populationc (n = 16)
    1 (≥12 to <18 yr)2 (≥6 to <12 yr)3 (≥2 to <6 yr)4 (≥3 mo to <2 yr)
    Ceftazidime230.6 (30.7)221.2 (17.4)255.32 (43.95)286.27 (37.13)289.0d (15.4)
    Avibactam36.4 (33.6)34.8 (22.6)43.25 (12.14)48.99 (10.64)42.1e (16.0)
    • ↵a Data for cohorts 1 and 2 are geometric means (percent coefficients of variation).

    • ↵b Data for cohorts 3 and 4 are means (SD) based on population pharmacokinetic model predictions (42).

    • ↵c Values are geometric means (percent coefficients of variation) for observed exposures from a phase I study in healthy adult volunteers on day 1 after receiving a single dose of ceftazidime-avibactam (2,000 to 500 mg) (44).

    • ↵d n = 15.

    • ↵e n = 13.

  • TABLE 5

    Summary of AEs in cohorts 3 and 4 (safety analysis population)c

    System organ class/preferred termNo. (%) of patients with AE for cohortb:
    3 (≥2 to <6 yr)(n = 8)4 (≥3 mo to <2 yr)(n = 8)Totala (n = 32)
    Any4 (50.0)2 (25.0)6 (18.8)
    Cardiac disorders01 (12.5)1 (3.1)
        Sinus tachycardia01 (12.5)1 (3.1)
    Gastrointestinal disorders3 (37.5)03 (9.4)
        Constipation1 (12.5)01 (3.1)
        Diarrhea1 (12.5)01 (3.1)
        Vomiting1 (12.5)01 (3.1)
    Investigations1 (12.5)01 (3.1)
        Increased alanine aminotransferase1 (12.5)01 (3.1)
        Increased aspartate aminotransferase1 (12.5)01 (3.1)
        Increased blood triglycerides1 (12.5)01 (3.1)
        Increased gamma-glutamyltransferase1 (12.5)01 (3.1)
    Injury, poisoning, and procedural complications01 (12.5)1 (3.1)
        Procedural site reaction01 (12.5)1 (3.1)
    • ↵a Total patient number includes cohorts 1 to 4.

    • ↵b Onset on or after the date and time of the first dose of ceftazidime-avibactam and up to and including the day 3 follow-up visit.

    • ↵c No AEs were reported in cohorts 1 and 2.

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Phase I Study Assessing the Pharmacokinetic Profile, Safety, and Tolerability of a Single Dose of Ceftazidime-Avibactam in Hospitalized Pediatric Patients
John S. Bradley, Jon Armstrong, Antonio Arrieta, Raafat Bishai, Shampa Das, Shirley Delair, Timi Edeki, William C. Holmes, Jianguo Li, Kathryn S. Moffett, Deepa Mukundan, Norma Perez, José R. Romero, David Speicher, Janice E. Sullivan, Diansong Zhou
Antimicrobial Agents and Chemotherapy Sep 2016, 60 (10) 6252-6259; DOI: 10.1128/AAC.00862-16

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Phase I Study Assessing the Pharmacokinetic Profile, Safety, and Tolerability of a Single Dose of Ceftazidime-Avibactam in Hospitalized Pediatric Patients
John S. Bradley, Jon Armstrong, Antonio Arrieta, Raafat Bishai, Shampa Das, Shirley Delair, Timi Edeki, William C. Holmes, Jianguo Li, Kathryn S. Moffett, Deepa Mukundan, Norma Perez, José R. Romero, David Speicher, Janice E. Sullivan, Diansong Zhou
Antimicrobial Agents and Chemotherapy Sep 2016, 60 (10) 6252-6259; DOI: 10.1128/AAC.00862-16
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