Candidemia, Candidiasis
Conditions
Keywords
Open-Label, Pharmacokinetics, Intravenous to oral switch, Safety, Voriconazole, Immunocompromise, Children, High Risk For Systemic Fungal Infection.
Brief summary
In this study we will measure the concentration of the drug called voriconazole which is used to fight infections caused by fungus in children who usually are cancer patients and have their immune system down. Since we know the dose in adults, and we think we know the matching doses in the young patients ages 2 to 12 years old, we will compare the amount of drug that goes into the system with what we know works in adults. We give the drug by a needle directly into the blood, then few days later we stop that and give the drug by mouth. Meanwhile, we draw a little bit of blood at certain times to measure the drug in it.
Interventions
Study Days 1 to 7: IV voriconazole 7 mg/kg q12h. Study Days 8 to 14: Oral voriconazole (POS) 200 mg q12h Notes: 1. If unable to switch to oral medication on Day 8, subjects can continue with IV treatment up to Day 20 before switching to oral dose. 2. Only morning oral dose will be given on Day 14 (or the seventh day of oral dosing if IV regimen is extended). However, if clinically indicated, voriconazole treatment may be continued up to Day 30. (IV = Intravenous; POS = Powder for oral suspension)
Sponsors
Pfizer
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
2 Years to 11 Years
Healthy volunteers
No
Inclusion criteria
* Male or female from 2 to \<12 years of age. * Require treatment for the prevention of systemic fungal infection. * Expected to develop neutropenia (ANC \<500 cells/μL) lasting more than 10 days following chemotherapy. * Anticipated to live for more than 3 months.
Exclusion criteria
* Evidence of any clinically significant liver or renal function or other abnormalities such as cardiac arrhythmia, hypokalemia, hypomagnesemia or hypocalcemia. * Documented bacterial or viral infection not responding to appropriate treatment. * Hypersensitivity to or severe intolerance of azole antifungal agents. * Receiving other azoles or drugs that is are prohibited in the voriconazole label or associated.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Curve Over Dosing Interval at Steady State (AUC12,ss) Following IV Administration | Day 7 (up to Day 20 or more) at predose, 60 and 138 minutes, 4, 6, 8 and 12 hours postdose | AUC12,ss = Area under the plasma concentration-time profile from time zero (predose) to twelve hours at steady-state. AUC12,ss was obtained by the Linear/Log trapezoidal method. |
| Peak Plasma Concentration at Steady State (Cmax,ss) Following IV Administration | Day 7 (up to Day 20 or more) at predose, 60 and 138 minutes, 4, 6, 8 and 12 hours postdose | — |
| Time to Reach Cmax (Tmax) Following IV Administration | Day 7 (up to Day 20 or more) at predose, 60 and 138 minutes, 4, 6, 8 and 12 hours postdose | — |
| AUC12,ss Following Oral Administration | Day 7 (or later) predose, 1, 2, 4, 6, 8 and 12 hours postdose | AUC12,ss = Area under the plasma concentration-time profile from time zero (predose) to twelve hours at steady-state. AUC12,ss was obtained by the Linear/Log trapezoidal method. |
| Cmax,ss Following Oral Administration | Day 7 (or later) predose, 1, 2, 4, 6, 8 and 12 hours postdose | — |
| Tmax Following Oral Administration | Day 7 (or later) predose, 1, 2, 4, 6, 8 and 12 hours postdose | — |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Tmax of N-oxide Voriconazole Metabolite (UK-121, 265) Following IV Administration | Days 1 and 7 (up to Day 20 or more) predose, 60 and 138 minutes, 4, 6, 8 and 12 hours postdose | Zero Tmax refers to the highest concentration observed for one participant at predose. The profile of the metabolite is relatively flat, which could result in slight variation in sample collection or assay process. |
| AUC12,ss of N-oxide Voriconazole Metabolite (UK-121, 265) Following Oral Administration | Day 7 (or later) predose, 1, 2, 4, 6, 8 and 12 hours postdose | AUC12,ss = Area under the plasma concentration-time profile from time zero (predose) to twelve hours at steady-state. AUC12,ss was obtained by the Linear/Log trapezoidal method. |
| AUC12 Following IV Loading Dose | Day 1 predose, 60 and 138 minutes, 4, 6, 8 and 12 hours postdose | AUC12 = Area under the plasma concentration-time profile from time zero (predose) to twelve hours. AUC12 was obtained by the Linear/Log trapezoidal method. |
| Tmax of N-oxide Voriconazole Metabolite (UK-121, 265) Following Oral Administration | Day 7 (or later) predose, 1, 2, 4, 6, 8 and 12 hours postdose | — |
| Cmax,ss of N-oxide Voriconazole Metabolite (UK-121, 265) Following Oral Administration | Day 7 (or later) predose, 1, 2, 4, 6, 8 and 12 hours postdose | — |
| Cmax Following an IV Loading Dose | Day 1 predose, 60 and 138 minutes, 4, 6, 8 and 12 hours postdose | — |
| Tmax Following an IV Loading Dose | Day 1 predose, 60 and 138 minutes, 4, 6, 8 and 12 hours postdose | — |
| Trough Concentrations (Cmin) | Day 7 (up to Day 20 or more) for IV; Day 7 (or later) for oral at predose | — |
| AUC12,ss of N-oxide Voriconazole Metabolite (UK-121, 265) Following IV Administration | Days 1 and 7 (up to Day 20 or more) predose, 60 and 138 minutes, 4, 6, 8 and 12 hours postdose | AUC12,ss = Area under the plasma concentration-time profile from time zero (predose) to twelve hours at steady-state. AUC12,ss was obtained by the Linear/Log trapezoidal method. |
| Cmax,ss of N-oxide Voriconazole Metabolite (UK-121, 265) Following IV Administration | Days 1 and 7 (up to Day 20 or more) predose, 60 and 138 minutes, 4, 6, 8 and 12 hours postdose | — |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| All Participants Voriconazole IV multiple dose (7 mg/kg once every 12 hours) was administered in the morning and evening on Days 1 to 7 (up to Day 20 or more if clinically indicated). The oral maintenance dosing regimen (200 mg every 12 hours) was administered following voriconazole IV in the morning and evening and lasted 6.5 days (up to Day 30 if clinically indicated). | 40 |
| Total | 40 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Voriconazole IV | Adverse Event | 6 |
| Voriconazole Oral | Other | 3 |
Baseline characteristics
| Characteristic | All Participants |
|---|---|
| Age, Customized 2 to <6 years | 24 Participants |
| Age, Customized 6 to <12 years | 16 Participants |
| Sex: Female, Male Female | 17 Participants |
| Sex: Female, Male Male | 23 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 39 / 40 | 34 / 34 |
| serious Total, serious adverse events | 6 / 40 | 13 / 34 |
Outcome results
Primary
Area Under the Curve Over Dosing Interval at Steady State (AUC12,ss) Following IV Administration
AUC12,ss = Area under the plasma concentration-time profile from time zero (predose) to twelve hours at steady-state. AUC12,ss was obtained by the Linear/Log trapezoidal method.
Time frame: Day 7 (up to Day 20 or more) at predose, 60 and 138 minutes, 4, 6, 8 and 12 hours postdose
Population: Intent-to treat (ITT) population of participants who had completed pharmacokinetic (PK) blood sampling for at least one day. N = number of participants with analyzable data.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Voriconazole IV | Area Under the Curve Over Dosing Interval at Steady State (AUC12,ss) Following IV Administration | 21.42 μg*h/mL | Standard Deviation 35.05 |
Primary
AUC12,ss Following Oral Administration
AUC12,ss = Area under the plasma concentration-time profile from time zero (predose) to twelve hours at steady-state. AUC12,ss was obtained by the Linear/Log trapezoidal method.
Time frame: Day 7 (or later) predose, 1, 2, 4, 6, 8 and 12 hours postdose
Population: ITT population of participants who had completed PK blood sampling for at least one day. N = number of participants with analyzable data.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Voriconazole IV | AUC12,ss Following Oral Administration | 18.64 μg*h/mL | Standard Deviation 50.63 |
Primary
Cmax,ss Following Oral Administration
Time frame: Day 7 (or later) predose, 1, 2, 4, 6, 8 and 12 hours postdose
Population: ITT population of participants who had completed PK blood sampling for at least one day. N = number of participants with analyzable data.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Voriconazole IV | Cmax,ss Following Oral Administration | 3.62 μg/mL | Standard Deviation 4.66 |
Primary
Peak Plasma Concentration at Steady State (Cmax,ss) Following IV Administration
Time frame: Day 7 (up to Day 20 or more) at predose, 60 and 138 minutes, 4, 6, 8 and 12 hours postdose
Population: ITT population of participants who had completed PK blood sampling for at least one day. N = number of participants with analyzable data.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Voriconazole IV | Peak Plasma Concentration at Steady State (Cmax,ss) Following IV Administration | 4.26 μg/mL | Standard Deviation 3.73 |
Primary
Time to Reach Cmax (Tmax) Following IV Administration
Time frame: Day 7 (up to Day 20 or more) at predose, 60 and 138 minutes, 4, 6, 8 and 12 hours postdose
Population: ITT population of participants who had completed PK blood sampling for at least one day. N = number of participants with analyzable data.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Voriconazole IV | Time to Reach Cmax (Tmax) Following IV Administration | 2.30 hours |
Primary
Tmax Following Oral Administration
Time frame: Day 7 (or later) predose, 1, 2, 4, 6, 8 and 12 hours postdose
Population: ITT population of participants who had completed PK blood sampling for at least one day. N = number of participants with analyzable data.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Voriconazole IV | Tmax Following Oral Administration | 1.07 hours |
Secondary
AUC12 Following IV Loading Dose
AUC12 = Area under the plasma concentration-time profile from time zero (predose) to twelve hours. AUC12 was obtained by the Linear/Log trapezoidal method.
Time frame: Day 1 predose, 60 and 138 minutes, 4, 6, 8 and 12 hours postdose
Population: ITT population of participants who had completed PK blood sampling for at least one day. N = number of participants with analyzable data.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Voriconazole IV | AUC12 Following IV Loading Dose | 7.85 μg*h/mL | Standard Deviation 6.71 |
Secondary
AUC12,ss of N-oxide Voriconazole Metabolite (UK-121, 265) Following IV Administration
AUC12,ss = Area under the plasma concentration-time profile from time zero (predose) to twelve hours at steady-state. AUC12,ss was obtained by the Linear/Log trapezoidal method.
Time frame: Days 1 and 7 (up to Day 20 or more) predose, 60 and 138 minutes, 4, 6, 8 and 12 hours postdose
Population: ITT population of participants who had completed PK blood sampling for at least one day. N = number of participants with analyzable data.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Voriconazole IV | AUC12,ss of N-oxide Voriconazole Metabolite (UK-121, 265) Following IV Administration | Day 1 | 20.98 μg*h/mL | Standard Deviation 8.05 |
| Voriconazole IV | AUC12,ss of N-oxide Voriconazole Metabolite (UK-121, 265) Following IV Administration | Day 7 (up to Day 20) | 41.95 μg*h/mL | Standard Deviation 14.3 |
Secondary
AUC12,ss of N-oxide Voriconazole Metabolite (UK-121, 265) Following Oral Administration
AUC12,ss = Area under the plasma concentration-time profile from time zero (predose) to twelve hours at steady-state. AUC12,ss was obtained by the Linear/Log trapezoidal method.
Time frame: Day 7 (or later) predose, 1, 2, 4, 6, 8 and 12 hours postdose
Population: ITT population of participants who had completed PK blood sampling for at least one day. N = number of participants with analyzable data.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Voriconazole IV | AUC12,ss of N-oxide Voriconazole Metabolite (UK-121, 265) Following Oral Administration | 51.65 μg*h/mL | Standard Deviation 27.88 |
Secondary
Cmax Following an IV Loading Dose
Time frame: Day 1 predose, 60 and 138 minutes, 4, 6, 8 and 12 hours postdose
Population: ITT population of participants who had completed PK blood sampling for at least one day. N = number of participants with analyzable data.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Voriconazole IV | Cmax Following an IV Loading Dose | 2.15 μg/mL | Standard Deviation 1.1 |
Secondary
Cmax,ss of N-oxide Voriconazole Metabolite (UK-121, 265) Following IV Administration
Time frame: Days 1 and 7 (up to Day 20 or more) predose, 60 and 138 minutes, 4, 6, 8 and 12 hours postdose
Population: ITT population of participants who had completed PK blood sampling for at least one day. N = number of participants with analyzable data.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Voriconazole IV | Cmax,ss of N-oxide Voriconazole Metabolite (UK-121, 265) Following IV Administration | Day 1 | 2.97 μg/mL | Standard Deviation 0.94 |
| Voriconazole IV | Cmax,ss of N-oxide Voriconazole Metabolite (UK-121, 265) Following IV Administration | Day 7 (up to Day 20) | 4.47 μg/mL | Standard Deviation 1.44 |
Secondary
Cmax,ss of N-oxide Voriconazole Metabolite (UK-121, 265) Following Oral Administration
Time frame: Day 7 (or later) predose, 1, 2, 4, 6, 8 and 12 hours postdose
Population: ITT population of participants who had completed PK blood sampling for at least one day. N = number of participants with analyzable data.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Voriconazole IV | Cmax,ss of N-oxide Voriconazole Metabolite (UK-121, 265) Following Oral Administration | 5.62 μg/mL | Standard Deviation 2.54 |
Secondary
Tmax Following an IV Loading Dose
Time frame: Day 1 predose, 60 and 138 minutes, 4, 6, 8 and 12 hours postdose
Population: ITT population of participants who had completed PK blood sampling for at least one day. N = number of participants with analyzable data.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Voriconazole IV | Tmax Following an IV Loading Dose | 2.30 hours |
Secondary
Tmax of N-oxide Voriconazole Metabolite (UK-121, 265) Following IV Administration
Zero Tmax refers to the highest concentration observed for one participant at predose. The profile of the metabolite is relatively flat, which could result in slight variation in sample collection or assay process.
Time frame: Days 1 and 7 (up to Day 20 or more) predose, 60 and 138 minutes, 4, 6, 8 and 12 hours postdose
Population: ITT population of participants who had completed PK blood sampling for at least one day. N=number of participants with analyzable data.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Voriconazole IV | Tmax of N-oxide Voriconazole Metabolite (UK-121, 265) Following IV Administration | Day 1 | 4.00 hours |
| Voriconazole IV | Tmax of N-oxide Voriconazole Metabolite (UK-121, 265) Following IV Administration | Day 7 (up to Day 20) | 4.00 hours |
Secondary
Tmax of N-oxide Voriconazole Metabolite (UK-121, 265) Following Oral Administration
Time frame: Day 7 (or later) predose, 1, 2, 4, 6, 8 and 12 hours postdose
Population: ITT population of participants who had completed PK blood sampling for at least one day. N = number of participants with analyzable data.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Voriconazole IV | Tmax of N-oxide Voriconazole Metabolite (UK-121, 265) Following Oral Administration | 3.97 hours |
Secondary
Trough Concentrations (Cmin)
Time frame: Day 7 (up to Day 20 or more) for IV; Day 7 (or later) for oral at predose
Population: ITT population of participants who had completed PK blood sampling for at least one day. N = number of participants with analyzable data; n = number of participants who contributed to data.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Voriconazole IV | Trough Concentrations (Cmin) | IV Day 7 (up to Day 20) (n=36) | 0.61 μg/mL | Standard Deviation 2.56 |
| Voriconazole IV | Trough Concentrations (Cmin) | Oral Day 7 (up to Day 30) (n=32) | 0.52 μg/mL | Standard Deviation 3.32 |