Neutropenia
Conditions
Brief summary
This study aims to evaluate the pharmacokinetics of posaconazole (POS) administered intravenously (IV) or orally to immunocompromised pediatric participants.
Interventions
DRUGPosaconazole IV solution
Posaconazole by IV solution twice on Day 1, then once daily on Days 2-10.
DRUGPosaconazole powder for oral suspension
Posaconazole once daily by PFS for a minimum of 10 days
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
2 Years to 17 Years
Healthy volunteers
No
Inclusion criteria
* Have documented or anticipated neutropenia expected to last for at least 7 days, following treatment in at least one of the following clinical situations: acute leukemia, myelodysplasia, severe aplastic anemia, recipients of Autologous Hematopoietic Stem Cell Transplant (HSCT), high risk neuroblastoma, advanced stage non-Hodgkin's lymphoma, hemophagocytic lymphohistiocytosis * Have a central line in place prior to IV study therapy * Participants of reproductive potential agree to remain abstinent, or use a medically accepted method of birth control
Exclusion criteria
* Has a proven or probable invasive fungal infection * Has received any formulation of POS within prior 10 days * Is receiving any prohibited drugs * Has laboratory results that are outside of normal limits at screening, as follows: a) Moderate or severe liver dysfunction, as defined as: Aspartate Aminotransferase (AST) \> 5 times the upper limit of normal (ULN), OR Alanine Aminotransferase (ALT) \> 5 times the ULN, OR Serum total bilirubin \>2.5 times the ULN, OR AST or ALT \> 3 times ULN with total bilirubin \> 2 times ULN; b) Calculated creatinine clearance \<30 mL/min. * Has QTc (QT interval corrected for rate) prolongation defined as: a) Symptomatic QTc prolongation \>450 msec (males) or \>470 msec (females) OR b) Any QTc prolongation of \>500 msec * Is pregnant, intends to become pregnant during study, or is breastfeeding * Has a history of anaphylaxis attributed to the azole class of antifungal agents * Is not expected to receive a minimum of 10 days of POS IV solution * Has participated in any Phase 1 Investigational New Drug (IND) study within prior 30 days or expects to do so within the following 60 days * Is or has an immediate family member (e.g., spouse, parent/legal guardian, sibling or child) who is investigational site or sponsor staff directly involved with this trial
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Apparent Total Body Clearance (CL/F) for POS Administered by PFS | Any day from Day 7 to Day 10 of therapy (up to 28 days) at pre-dose, within 15 minutes after end of infusion (up to 2 hours), and 4, 6, 8, 12, 24 hours post-infusion | Blood was collected from pre-dose up to 24 hours post-dose in order to determine the plasma CL/F of posaconazole administered by PFS. A non-compartmental analysis of posaconazole plasma concentrations was performed. Results are reported for participants that received PFS treatment. |
| Time of Maximum Plasma Concentration (Tmax) for POS | Any day from Day 7 to Day 10 of therapy for each formulation (up to 28 days) at pre-dose, within 15 minutes after end of infusion (up to 2 hours), and 4, 6, 8, 12, 24 hours post-infusion | Blood was collected from pre-dose up to 24 hours post-dose in order to determine the plasma Tmax of posaconazole. A non-compartmental analysis of posaconazole plasma concentrations was performed. Results are reported for each treatment arm according to the formulation that participants received (IV or PFS). Participants receiving both formulations were counted once for each formulation. |
| Total Body Clearance (CL) for POS Administered by IV | Any day from Day 7 to Day 10 of therapy (up to 28 days) at pre-dose, within 15 minutes after end of infusion (up to 2 hours), and 4, 6, 8, 12, 24 hours post-infusion | Blood was collected from pre-dose up to 24 hours post-dose in order to determine the plasma CL of posaconazole administered by IV. A non-compartmental analysis of posaconazole plasma concentrations was performed. Results are reported for participants that received IV treatment. |
| Area Under the Plasma Concentration Versus Time Curve (AUC) From Time 0 to 24 Hours Post-dose for POS | Any day from Day 7 to Day 10 of therapy for each formulation (up to 28 days) at pre-dose, within 15 minutes after end of infusion (up to 2 hours), and 4, 6, 8, 12, 24 hours post-infusion | Blood was collected from pre-dose up to 24 hours post-dose in order to determine the plasma AUC from time 0-24 hours post-dose (AUC0-24hr) of posaconazole. A non compartmental analysis of posaconazole plasma concentrations was performed. Results are reported for each treatment arm according to the formulation that participants received (IV or PFS). Participants receiving both formulations were counted once for each formulation. |
| Maximum Plasma Concentration (Cmax) for POS | Any day from Day 7 to Day 10 of therapy for each formulation (up to 28 days) at pre-dose, within 15 minutes after end of infusion (up to 2 hours), and 4, 6, 8, 12, 24 hours post-infusion | Blood was collected from pre-dose up to 24 hours post-dose in order to determine the plasma Cmax of posaconazole. A non-compartmental analysis of posaconazole plasma concentrations was performed. Results are reported for each treatment arm according to the formulation that participants received (IV or PFS). Participants receiving both formulations were counted once for each formulation. |
| Minimum Plasma Concentration (Cmin) for POS | Any day from Day 7 to Day 10 of therapy for each formulation (up to 28 days) at pre-dose, within 15 minutes after end of infusion (up to 2 hours), and 4, 6, 8, 12, 24 hours post-infusion | Blood was collected from pre-dose up to 24 hours post-dose in order to determine the plasma Cmin of posaconazole. A non-compartmental analysis of posaconazole plasma concentrations was performed. Results are reported for each treatment arm according to the formulation that participants received (IV or PFS). Participants receiving both formulations were counted once for each formulation. |
| Average Steady-state Plasma Concentration (Cavg) for POS | Any day from Day 7 to Day 10 of therapy for each formulation (up to 28 days) at pre-dose, within 15 minutes after end of infusion (up to 2 hours), and 4, 6, 8, 12, 24 hours post-infusion | Blood was collected from pre-dose up to 24 hours post-dose in order to determine the plasma Cavg of posaconazole. A non-compartmental analysis of posaconazole plasma concentrations was performed. Results are reported for each treatment arm according to the formulation that participants received (IV or PFS). Participants receiving both formulations were counted once for each formulation. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Who Discontinued Treatment of Study Drug Due to an Adverse Event (AE) | Up to 28 days | An adverse event (AE) is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product or protocol - specified procedure. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition that is temporally associated with the use of the Sponsor's product, is also an AE. |
| Number of Participants With an Adverse Event (AE) | 14 days after end of treatment (Up to 42 days) | An adverse event (AE) is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product or protocol - specified procedure. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition that is temporally associated with the use of the Sponsor's product, is also an AE. |
Participant flow
Recruitment details
Immunocompromised participants aged 2 to 17 years old, with neutropenia expected to last for at least 7 days following start of study treatment, were enrolled in this study.
Participants by arm
| Arm | Count |
|---|---|
| 3.5 mg/kg POS (2<7 Years Old) Children 2 to less than 7 years of age received posaconazole (POS) at 3.5 mg/kg by intravenous (IV) solution twice on Day 1, then once daily on Days 2-10. This was followed by treatment with 3.5 mg/kg POS once daily by powder for oral suspension (PFS) for a minimum of 10 days; or, if they were unwilling or unable to tolerate POS PFS, continued treatment with POS IV. | 16 |
| 3.5 mg/kg POS (7-17 Years Old) Children 7 to 17 years of age received POS at 3.5 mg/kg by IV solution twice on Day 1, then once daily on Days 2-10. This was followed by treatment with 3.5 mg/kg POS once daily by PFS for a minimum of 10 days; or, if they were unwilling or unable to tolerate POS PFS, continued treatment with POS IV. | 21 |
| 4.5 mg/kg POS (2<7 Years Old) Children 2 to less than 7 years of age received POS at 4.5 mg/kg by IV solution twice on Day 1, then once daily on Days 2-10. This was followed by treatment with 4.5 mg/kg POS once daily by PFS for a minimum of 10 days; or, if they were unwilling or unable to tolerate POS PFS, continued treatment with POS IV. | 15 |
| 4.5 mg/kg POS (7-17 Years Old) Children 7 to 17 years of age received POS at 4.5 mg/kg by IV solution twice on Day 1, then once daily on Days 2-10. This was followed by treatment with 4.5 mg/kg POS once daily by PFS for a minimum of 10 days; or, if they were unwilling or unable to tolerate POS PFS, continued treatment with POS IV. | 17 |
| 6 mg/kg POS (2<7 Years Old) Children 2 to less than 7 years of age received POS at 6 mg/kg by IV solution twice on Day 1, then once daily on Days 2-10. This was followed by treatment with 6 mg/kg POS once daily by PFS for a minimum of 10 days; or, if they were unwilling or unable to tolerate POS PFS, continued treatment with POS IV. | 20 |
| 6 mg/kg POS (7-17 Years Old) Children 7 to 17 years of age received POS at 6 mg/kg by IV solution twice on Day 1, then once daily on Days 2-10. This was followed by treatment with 6 mg/kg POS once daily by PFS for a minimum of 10 days; or, if they were unwilling or unable to tolerate POS PFS, continued treatment with POS IV. | 29 |
| Total | 118 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 0 | 0 | 0 | 0 | 1 |
| Overall Study | Death | 0 | 0 | 0 | 0 | 1 | 1 |
| Overall Study | Physician Decision | 0 | 1 | 1 | 0 | 0 | 0 |
| Overall Study | Protocol Violation | 0 | 0 | 0 | 0 | 0 | 1 |
| Overall Study | Screen Failure | 1 | 0 | 0 | 1 | 0 | 0 |
| Overall Study | Withdrawn by Parent/Guardian | 1 | 0 | 0 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | 3.5 mg/kg POS (2<7 Years Old) | 3.5 mg/kg POS (7-17 Years Old) | 4.5 mg/kg POS (2<7 Years Old) | 4.5 mg/kg POS (7-17 Years Old) | 6 mg/kg POS (2<7 Years Old) | 6 mg/kg POS (7-17 Years Old) | Total |
|---|---|---|---|---|---|---|---|
| Age, Continuous | 3.9 Years STANDARD_DEVIATION 1.5 | 13.9 Years STANDARD_DEVIATION 2.1 | 4.1 Years STANDARD_DEVIATION 1.4 | 12.5 Years STANDARD_DEVIATION 2.7 | 3.9 Years STANDARD_DEVIATION 1.6 | 12.0 Years STANDARD_DEVIATION 3.5 | 8.9 Years STANDARD_DEVIATION 5 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 2 Participants | 2 Participants | 4 Participants | 1 Participants | 2 Participants | 12 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 15 Participants | 19 Participants | 12 Participants | 12 Participants | 18 Participants | 27 Participants | 103 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 1 Participants | 1 Participants | 1 Participants | 0 Participants | 3 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 4 Participants | 1 Participants | 2 Participants | 2 Participants | 1 Participants | 1 Participants | 11 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 2 Participants | 3 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 2 Participants | 0 Participants | 2 Participants | 0 Participants | 0 Participants | 4 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 12 Participants | 18 Participants | 12 Participants | 13 Participants | 18 Participants | 26 Participants | 99 Participants |
| Sex: Female, Male Female | 3 Participants | 11 Participants | 8 Participants | 8 Participants | 10 Participants | 10 Participants | 50 Participants |
| Sex: Female, Male Male | 13 Participants | 10 Participants | 7 Participants | 9 Participants | 10 Participants | 19 Participants | 68 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 14 | 0 / 21 | 0 / 15 | 0 / 16 | 1 / 20 | 2 / 29 |
| other Total, other adverse events | 13 / 14 | 20 / 21 | 15 / 15 | 16 / 16 | 19 / 20 | 29 / 29 |
| serious Total, serious adverse events | 3 / 14 | 8 / 21 | 4 / 15 | 5 / 16 | 3 / 20 | 8 / 29 |
Outcome results
Primary
Apparent Total Body Clearance (CL/F) for POS Administered by PFS
Blood was collected from pre-dose up to 24 hours post-dose in order to determine the plasma CL/F of posaconazole administered by PFS. A non-compartmental analysis of posaconazole plasma concentrations was performed. Results are reported for participants that received PFS treatment.
Time frame: Any day from Day 7 to Day 10 of therapy (up to 28 days) at pre-dose, within 15 minutes after end of infusion (up to 2 hours), and 4, 6, 8, 12, 24 hours post-infusion
Population: All treated participants who received at least 7 days of POS PFS therapy, completed the full POS PK sampling while on POS PFS, and met pre-specified acceptability criteria.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| 3.5 mg/kg POS (2<7 Years Old) | Apparent Total Body Clearance (CL/F) for POS Administered by PFS | 4.97 L/hr | Geometric Coefficient of Variation 29.1 |
| 3.5 mg/kg POS (7-17 Years Old) | Apparent Total Body Clearance (CL/F) for POS Administered by PFS | 7.67 L/hr | Geometric Coefficient of Variation 39.9 |
| 4.5 mg/kg POS (2<7 Years Old) | Apparent Total Body Clearance (CL/F) for POS Administered by PFS | 3.49 L/hr | Geometric Coefficient of Variation 59.1 |
| 4.5 mg/kg POS (7-17 Years Old) | Apparent Total Body Clearance (CL/F) for POS Administered by PFS | 7.84 L/hr | Geometric Coefficient of Variation 49.4 |
| 6 mg/kg POS (2<7 Years Old) | Apparent Total Body Clearance (CL/F) for POS Administered by PFS | 4.60 L/hr | Geometric Coefficient of Variation 35.2 |
| 6 mg/kg POS (7-17 Years Old) | Apparent Total Body Clearance (CL/F) for POS Administered by PFS | 8.39 L/hr | Geometric Coefficient of Variation 190.3 |
Primary
Area Under the Plasma Concentration Versus Time Curve (AUC) From Time 0 to 24 Hours Post-dose for POS
Blood was collected from pre-dose up to 24 hours post-dose in order to determine the plasma AUC from time 0-24 hours post-dose (AUC0-24hr) of posaconazole. A non compartmental analysis of posaconazole plasma concentrations was performed. Results are reported for each treatment arm according to the formulation that participants received (IV or PFS). Participants receiving both formulations were counted once for each formulation.
Time frame: Any day from Day 7 to Day 10 of therapy for each formulation (up to 28 days) at pre-dose, within 15 minutes after end of infusion (up to 2 hours), and 4, 6, 8, 12, 24 hours post-infusion
Population: All treated participants who received at least 7 days of POS dosing (IV and PFS), completed the full POS PK sampling, and met pre-specifiied acceptability criteria.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| 3.5 mg/kg POS (2<7 Years Old) | Area Under the Plasma Concentration Versus Time Curve (AUC) From Time 0 to 24 Hours Post-dose for POS | IV | 17800 hr*ng/mL | Geometric Coefficient of Variation 55 |
| 3.5 mg/kg POS (2<7 Years Old) | Area Under the Plasma Concentration Versus Time Curve (AUC) From Time 0 to 24 Hours Post-dose for POS | PFS | 12200 hr*ng/mL | Geometric Coefficient of Variation 36 |
| 3.5 mg/kg POS (7-17 Years Old) | Area Under the Plasma Concentration Versus Time Curve (AUC) From Time 0 to 24 Hours Post-dose for POS | IV | 27300 hr*ng/mL | Geometric Coefficient of Variation 49.7 |
| 3.5 mg/kg POS (7-17 Years Old) | Area Under the Plasma Concentration Versus Time Curve (AUC) From Time 0 to 24 Hours Post-dose for POS | PFS | 20700 hr*ng/mL | Geometric Coefficient of Variation 33.8 |
| 4.5 mg/kg POS (2<7 Years Old) | Area Under the Plasma Concentration Versus Time Curve (AUC) From Time 0 to 24 Hours Post-dose for POS | IV | 25600 hr*ng/mL | Geometric Coefficient of Variation 30 |
| 4.5 mg/kg POS (2<7 Years Old) | Area Under the Plasma Concentration Versus Time Curve (AUC) From Time 0 to 24 Hours Post-dose for POS | PFS | 21600 hr*ng/mL | Geometric Coefficient of Variation 64.5 |
| 4.5 mg/kg POS (7-17 Years Old) | Area Under the Plasma Concentration Versus Time Curve (AUC) From Time 0 to 24 Hours Post-dose for POS | IV | 29800 hr*ng/mL | Geometric Coefficient of Variation 42.9 |
| 4.5 mg/kg POS (7-17 Years Old) | Area Under the Plasma Concentration Versus Time Curve (AUC) From Time 0 to 24 Hours Post-dose for POS | PFS | 28700 hr*ng/mL | Geometric Coefficient of Variation 33.7 |
| 6 mg/kg POS (2<7 Years Old) | Area Under the Plasma Concentration Versus Time Curve (AUC) From Time 0 to 24 Hours Post-dose for POS | IV | 31100 hr*ng/mL | Geometric Coefficient of Variation 48.9 |
| 6 mg/kg POS (2<7 Years Old) | Area Under the Plasma Concentration Versus Time Curve (AUC) From Time 0 to 24 Hours Post-dose for POS | PFS | 23000 hr*ng/mL | Geometric Coefficient of Variation 47.3 |
| 6 mg/kg POS (7-17 Years Old) | Area Under the Plasma Concentration Versus Time Curve (AUC) From Time 0 to 24 Hours Post-dose for POS | IV | 44200 hr*ng/mL | Geometric Coefficient of Variation 41.5 |
| 6 mg/kg POS (7-17 Years Old) | Area Under the Plasma Concentration Versus Time Curve (AUC) From Time 0 to 24 Hours Post-dose for POS | PFS | 25000 hr*ng/mL | Geometric Coefficient of Variation 184.3 |
Primary
Average Steady-state Plasma Concentration (Cavg) for POS
Blood was collected from pre-dose up to 24 hours post-dose in order to determine the plasma Cavg of posaconazole. A non-compartmental analysis of posaconazole plasma concentrations was performed. Results are reported for each treatment arm according to the formulation that participants received (IV or PFS). Participants receiving both formulations were counted once for each formulation.
Time frame: Any day from Day 7 to Day 10 of therapy for each formulation (up to 28 days) at pre-dose, within 15 minutes after end of infusion (up to 2 hours), and 4, 6, 8, 12, 24 hours post-infusion
Population: All treated participants who received at least 7 days of POS dosing (IV and PFS), completed the full POS PK sampling, and met pre-specifiied acceptability criteria.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| 3.5 mg/kg POS (2<7 Years Old) | Average Steady-state Plasma Concentration (Cavg) for POS | IV | 743 ng/mL | Geometric Coefficient of Variation 55 |
| 3.5 mg/kg POS (2<7 Years Old) | Average Steady-state Plasma Concentration (Cavg) for POS | PFS | 510 ng/mL | Geometric Coefficient of Variation 36 |
| 3.5 mg/kg POS (7-17 Years Old) | Average Steady-state Plasma Concentration (Cavg) for POS | IV | 1140 ng/mL | Geometric Coefficient of Variation 49.7 |
| 3.5 mg/kg POS (7-17 Years Old) | Average Steady-state Plasma Concentration (Cavg) for POS | PFS | 861 ng/mL | Geometric Coefficient of Variation 33.8 |
| 4.5 mg/kg POS (2<7 Years Old) | Average Steady-state Plasma Concentration (Cavg) for POS | IV | 1070 ng/mL | Geometric Coefficient of Variation 30 |
| 4.5 mg/kg POS (2<7 Years Old) | Average Steady-state Plasma Concentration (Cavg) for POS | PFS | 901 ng/mL | Geometric Coefficient of Variation 64.5 |
| 4.5 mg/kg POS (7-17 Years Old) | Average Steady-state Plasma Concentration (Cavg) for POS | IV | 1240 ng/mL | Geometric Coefficient of Variation 42.9 |
| 4.5 mg/kg POS (7-17 Years Old) | Average Steady-state Plasma Concentration (Cavg) for POS | PFS | 1200 ng/mL | Geometric Coefficient of Variation 33.7 |
| 6 mg/kg POS (2<7 Years Old) | Average Steady-state Plasma Concentration (Cavg) for POS | IV | 1300 ng/mL | Geometric Coefficient of Variation 48.9 |
| 6 mg/kg POS (2<7 Years Old) | Average Steady-state Plasma Concentration (Cavg) for POS | PFS | 960 ng/mL | Geometric Coefficient of Variation 47.3 |
| 6 mg/kg POS (7-17 Years Old) | Average Steady-state Plasma Concentration (Cavg) for POS | IV | 1840 ng/mL | Geometric Coefficient of Variation 41.5 |
| 6 mg/kg POS (7-17 Years Old) | Average Steady-state Plasma Concentration (Cavg) for POS | PFS | 1040 ng/mL | Geometric Coefficient of Variation 184.3 |
Primary
Maximum Plasma Concentration (Cmax) for POS
Blood was collected from pre-dose up to 24 hours post-dose in order to determine the plasma Cmax of posaconazole. A non-compartmental analysis of posaconazole plasma concentrations was performed. Results are reported for each treatment arm according to the formulation that participants received (IV or PFS). Participants receiving both formulations were counted once for each formulation.
Time frame: Any day from Day 7 to Day 10 of therapy for each formulation (up to 28 days) at pre-dose, within 15 minutes after end of infusion (up to 2 hours), and 4, 6, 8, 12, 24 hours post-infusion
Population: All treated participants who received at least 7 days of POS dosing (IV and PFS), completed the full POS PK sampling, and met pre-specifiied acceptability criteria.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| 3.5 mg/kg POS (2<7 Years Old) | Maximum Plasma Concentration (Cmax) for POS | IV | 1590 ng/mL | Geometric Coefficient of Variation 43.1 |
| 3.5 mg/kg POS (2<7 Years Old) | Maximum Plasma Concentration (Cmax) for POS | PFS | 884 ng/mL | Geometric Coefficient of Variation 44.4 |
| 3.5 mg/kg POS (7-17 Years Old) | Maximum Plasma Concentration (Cmax) for POS | IV | 2450 ng/mL | Geometric Coefficient of Variation 72.7 |
| 3.5 mg/kg POS (7-17 Years Old) | Maximum Plasma Concentration (Cmax) for POS | PFS | 1340 ng/mL | Geometric Coefficient of Variation 30.8 |
| 4.5 mg/kg POS (2<7 Years Old) | Maximum Plasma Concentration (Cmax) for POS | IV | 2320 ng/mL | Geometric Coefficient of Variation 39.8 |
| 4.5 mg/kg POS (2<7 Years Old) | Maximum Plasma Concentration (Cmax) for POS | PFS | 1550 ng/mL | Geometric Coefficient of Variation 40.8 |
| 4.5 mg/kg POS (7-17 Years Old) | Maximum Plasma Concentration (Cmax) for POS | IV | 2310 ng/mL | Geometric Coefficient of Variation 40.3 |
| 4.5 mg/kg POS (7-17 Years Old) | Maximum Plasma Concentration (Cmax) for POS | PFS | 1670 ng/mL | Geometric Coefficient of Variation 28.5 |
| 6 mg/kg POS (2<7 Years Old) | Maximum Plasma Concentration (Cmax) for POS | IV | 3060 ng/mL | Geometric Coefficient of Variation 54.1 |
| 6 mg/kg POS (2<7 Years Old) | Maximum Plasma Concentration (Cmax) for POS | PFS | 1510 ng/mL | Geometric Coefficient of Variation 43.4 |
| 6 mg/kg POS (7-17 Years Old) | Maximum Plasma Concentration (Cmax) for POS | IV | 3340 ng/mL | Geometric Coefficient of Variation 39.4 |
| 6 mg/kg POS (7-17 Years Old) | Maximum Plasma Concentration (Cmax) for POS | PFS | 1370 ng/mL | Geometric Coefficient of Variation 178.5 |
Primary
Minimum Plasma Concentration (Cmin) for POS
Blood was collected from pre-dose up to 24 hours post-dose in order to determine the plasma Cmin of posaconazole. A non-compartmental analysis of posaconazole plasma concentrations was performed. Results are reported for each treatment arm according to the formulation that participants received (IV or PFS). Participants receiving both formulations were counted once for each formulation.
Time frame: Any day from Day 7 to Day 10 of therapy for each formulation (up to 28 days) at pre-dose, within 15 minutes after end of infusion (up to 2 hours), and 4, 6, 8, 12, 24 hours post-infusion
Population: All treated participants who received at least 7 days of POS dosing (IV and PFS), completed the full POS PK sampling, and met pre-specifiied acceptability criteria.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| 3.5 mg/kg POS (2<7 Years Old) | Minimum Plasma Concentration (Cmin) for POS | IV | 400 ng/mL | Geometric Coefficient of Variation 81.3 |
| 3.5 mg/kg POS (2<7 Years Old) | Minimum Plasma Concentration (Cmin) for POS | PFS | 254 ng/mL | Geometric Coefficient of Variation 45.6 |
| 3.5 mg/kg POS (7-17 Years Old) | Minimum Plasma Concentration (Cmin) for POS | IV | 670 ng/mL | Geometric Coefficient of Variation 65.1 |
| 3.5 mg/kg POS (7-17 Years Old) | Minimum Plasma Concentration (Cmin) for POS | PFS | 579 ng/mL | Geometric Coefficient of Variation 44.9 |
| 4.5 mg/kg POS (2<7 Years Old) | Minimum Plasma Concentration (Cmin) for POS | IV | 501 ng/mL | Geometric Coefficient of Variation 56.8 |
| 4.5 mg/kg POS (2<7 Years Old) | Minimum Plasma Concentration (Cmin) for POS | PFS | 476 ng/mL | Geometric Coefficient of Variation 164.6 |
| 4.5 mg/kg POS (7-17 Years Old) | Minimum Plasma Concentration (Cmin) for POS | IV | 737 ng/mL | Geometric Coefficient of Variation 66 |
| 4.5 mg/kg POS (7-17 Years Old) | Minimum Plasma Concentration (Cmin) for POS | PFS | 790 ng/mL | Geometric Coefficient of Variation 48.2 |
| 6 mg/kg POS (2<7 Years Old) | Minimum Plasma Concentration (Cmin) for POS | IV | 626 ng/mL | Geometric Coefficient of Variation 104.8 |
| 6 mg/kg POS (2<7 Years Old) | Minimum Plasma Concentration (Cmin) for POS | PFS | 542 ng/mL | Geometric Coefficient of Variation 68.8 |
| 6 mg/kg POS (7-17 Years Old) | Minimum Plasma Concentration (Cmin) for POS | IV | 1160 ng/mL | Geometric Coefficient of Variation 60.4 |
| 6 mg/kg POS (7-17 Years Old) | Minimum Plasma Concentration (Cmin) for POS | PFS | 713 ng/mL | Geometric Coefficient of Variation 300.6 |
Primary
Time of Maximum Plasma Concentration (Tmax) for POS
Blood was collected from pre-dose up to 24 hours post-dose in order to determine the plasma Tmax of posaconazole. A non-compartmental analysis of posaconazole plasma concentrations was performed. Results are reported for each treatment arm according to the formulation that participants received (IV or PFS). Participants receiving both formulations were counted once for each formulation.
Time frame: Any day from Day 7 to Day 10 of therapy for each formulation (up to 28 days) at pre-dose, within 15 minutes after end of infusion (up to 2 hours), and 4, 6, 8, 12, 24 hours post-infusion
Population: All treated participants who received at least 7 days of POS dosing (IV and PFS), completed the full POS PK sampling, and met pre-specifiied acceptability criteria.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| 3.5 mg/kg POS (2<7 Years Old) | Time of Maximum Plasma Concentration (Tmax) for POS | IV | 1.78 Hours |
| 3.5 mg/kg POS (2<7 Years Old) | Time of Maximum Plasma Concentration (Tmax) for POS | PFS | 3.83 Hours |
| 3.5 mg/kg POS (7-17 Years Old) | Time of Maximum Plasma Concentration (Tmax) for POS | IV | 1.77 Hours |
| 3.5 mg/kg POS (7-17 Years Old) | Time of Maximum Plasma Concentration (Tmax) for POS | PFS | 2.20 Hours |
| 4.5 mg/kg POS (2<7 Years Old) | Time of Maximum Plasma Concentration (Tmax) for POS | IV | 1.78 Hours |
| 4.5 mg/kg POS (2<7 Years Old) | Time of Maximum Plasma Concentration (Tmax) for POS | PFS | 3.82 Hours |
| 4.5 mg/kg POS (7-17 Years Old) | Time of Maximum Plasma Concentration (Tmax) for POS | IV | 1.75 Hours |
| 4.5 mg/kg POS (7-17 Years Old) | Time of Maximum Plasma Concentration (Tmax) for POS | PFS | 6.14 Hours |
| 6 mg/kg POS (2<7 Years Old) | Time of Maximum Plasma Concentration (Tmax) for POS | IV | 1.75 Hours |
| 6 mg/kg POS (2<7 Years Old) | Time of Maximum Plasma Concentration (Tmax) for POS | PFS | 4.00 Hours |
| 6 mg/kg POS (7-17 Years Old) | Time of Maximum Plasma Concentration (Tmax) for POS | IV | 1.77 Hours |
| 6 mg/kg POS (7-17 Years Old) | Time of Maximum Plasma Concentration (Tmax) for POS | PFS | 2.78 Hours |
Primary
Total Body Clearance (CL) for POS Administered by IV
Blood was collected from pre-dose up to 24 hours post-dose in order to determine the plasma CL of posaconazole administered by IV. A non-compartmental analysis of posaconazole plasma concentrations was performed. Results are reported for participants that received IV treatment.
Time frame: Any day from Day 7 to Day 10 of therapy (up to 28 days) at pre-dose, within 15 minutes after end of infusion (up to 2 hours), and 4, 6, 8, 12, 24 hours post-infusion
Population: All treated participants who received at least 7 days of POS IV solution therapy, completed the full POS PK sampling while on POS IV solution, and met pre-specified acceptability criteria.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| 3.5 mg/kg POS (2<7 Years Old) | Total Body Clearance (CL) for POS Administered by IV | 3.39 L/hr | Geometric Coefficient of Variation 52.8 |
| 3.5 mg/kg POS (7-17 Years Old) | Total Body Clearance (CL) for POS Administered by IV | 6.64 L/hr | Geometric Coefficient of Variation 38.6 |
| 4.5 mg/kg POS (2<7 Years Old) | Total Body Clearance (CL) for POS Administered by IV | 2.97 L/hr | Geometric Coefficient of Variation 36.2 |
| 4.5 mg/kg POS (7-17 Years Old) | Total Body Clearance (CL) for POS Administered by IV | 6.69 L/hr | Geometric Coefficient of Variation 37.3 |
| 6 mg/kg POS (2<7 Years Old) | Total Body Clearance (CL) for POS Administered by IV | 3.27 L/hr | Geometric Coefficient of Variation 49.3 |
| 6 mg/kg POS (7-17 Years Old) | Total Body Clearance (CL) for POS Administered by IV | 4.76 L/hr | Geometric Coefficient of Variation 55.7 |
Secondary
Number of Participants Who Discontinued Treatment of Study Drug Due to an Adverse Event (AE)
An adverse event (AE) is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product or protocol - specified procedure. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition that is temporally associated with the use of the Sponsor's product, is also an AE.
Time frame: Up to 28 days
Population: All participants who received at least one dose of study drug. Data were analysed as pre-specified in the study protocol, based on age group and dosage, and did not distinguish oral from IV formulation.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| 3.5 mg/kg POS (2<7 Years Old) | Number of Participants Who Discontinued Treatment of Study Drug Due to an Adverse Event (AE) | 3 Participants |
| 3.5 mg/kg POS (7-17 Years Old) | Number of Participants Who Discontinued Treatment of Study Drug Due to an Adverse Event (AE) | 3 Participants |
| 4.5 mg/kg POS (2<7 Years Old) | Number of Participants Who Discontinued Treatment of Study Drug Due to an Adverse Event (AE) | 0 Participants |
| 4.5 mg/kg POS (7-17 Years Old) | Number of Participants Who Discontinued Treatment of Study Drug Due to an Adverse Event (AE) | 2 Participants |
| 6 mg/kg POS (2<7 Years Old) | Number of Participants Who Discontinued Treatment of Study Drug Due to an Adverse Event (AE) | 4 Participants |
| 6 mg/kg POS (7-17 Years Old) | Number of Participants Who Discontinued Treatment of Study Drug Due to an Adverse Event (AE) | 6 Participants |
Secondary
Number of Participants With an Adverse Event (AE)
An adverse event (AE) is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product or protocol - specified procedure. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition that is temporally associated with the use of the Sponsor's product, is also an AE.
Time frame: 14 days after end of treatment (Up to 42 days)
Population: All participants who received at least one dose of study drug. Data were analysed as pre-specified in the study protocol, based on age group and dosage, and did not distinguish oral from IV formulation.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| 3.5 mg/kg POS (2<7 Years Old) | Number of Participants With an Adverse Event (AE) | 13 Participants |
| 3.5 mg/kg POS (7-17 Years Old) | Number of Participants With an Adverse Event (AE) | 21 Participants |
| 4.5 mg/kg POS (2<7 Years Old) | Number of Participants With an Adverse Event (AE) | 15 Participants |
| 4.5 mg/kg POS (7-17 Years Old) | Number of Participants With an Adverse Event (AE) | 16 Participants |
| 6 mg/kg POS (2<7 Years Old) | Number of Participants With an Adverse Event (AE) | 19 Participants |
| 6 mg/kg POS (7-17 Years Old) | Number of Participants With an Adverse Event (AE) | 29 Participants |