Fungal Infection
Conditions
Brief summary
The purpose of this study is to evaluate the pharmacokinetics and safety of posaconazole intravenous solution in Chinese participants at high risk for invasive fungal infections. Neutropenic participants undergoing chemotherapy for acute myelogenous leukemia or myelodysplastic syndromes will be enrolled in the study. The primary hypothesis is to evaluate the pharmacokinetic parameters of intravenous (IV) posaconazole (POS) solution in Chinese participants at high risk of invasive fungal infections and determine the percentage of Chinese participants who reach steady-state concentration averages of POS in blood plasma of 500 ng/ml and higher. Two subgroups were evaluated: Subgroup 1 from serial PK blood draw sampling and Subgroup 2 from sparse limited PK blood draw sampling.
Interventions
DRUGPosaconazole
Posaconazole 18 mg/mL IV solution; posaconazole 40 mg/mL oral suspension
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
PREVENTION
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
* Chinese participant * Female of reproductive potential with a serum of beta human chorionic gonadotropin (β-hCG) level consistent with a nongravid state and agree and/or have their partner use 2 acceptable methods of birth control throughout the study * Body Mass Index (BMI) \>=15 and \<=30 kg/m\^2 * Have a central line catheter or peripherally central venous catheter in place * Anticipated or documented prolonged neutropenia and likely to last for at least 7 days due to: a) standard intensive chemotherapy, anthracycline-based or other accepted regimen (excluding any investigational agent) for a new diagnosis of acute myelogenous leukemia (AML); b)chemotherapy for AML in first relapse; or c) therapy for myelodysplastic syndromes in transformation to AML or other diagnoses of secondary AML (therapy related, antecedent hematological disorders) other than chronic myelogenous leukemia in blast crisis * Free from any clinically significant disease other than the primary hematologic disease that would interfere with administration of study medication or study evaluations * Able to tolerate central IV solution
Exclusion criteria
* Pregnant, intends to become pregnant during the study, or has been nursing * Mentally or legally incapacitated, has significant emotional problems, or has clinically significant psychiatric disorder over the last 5 years * Received systemic antifungal therapy (oral, intravenous, or inhaled) within 30 days of study enrollment for reasons other than antifungal prophylaxis * Known or suspected invasive or systemic fungal infection * Taken posaconazole within 10 days prior to study enrollment * Major surgery, donated or lost 1 unit of blood, or participated in another investigational study within 4 weeks prior to the study * Type 1 hypersensitivity or idiosyncratic reactions to azole agents * Significant multiple or severe allergies, or has had an anaphylactic reaction or significant intolerability to drugs or food * Moderate or severe liver dysfunction * Chronic active hepatitis, cirrhosis, Hepatocellular Carcinoma (HCC), or other hepatic disease caused by a virus * Previous electrocardiogram with a prolonged QTc interval * Prior enrollment in this study or other posaconazole studies within 90 days of study entry * Eastern Cooperative Oncology Group (ECOG) performance status was \>2 prior to induction chemotherapy for the underlying disease * Known or suspected Gilbert's disease.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| POS Plasma Trough Concentrations in the Serial PK and Sparse PK Subgroups | Day 3, Day 6, Day 10, Day 15, Day 22, Day 28 | Pre-dose plasma trough concentrations by study day between serial PK and Sparse PK - where serial PK is defined as multiple serial blood sampling of more than 6 timepoints; and sparse PK is defined as few blood samples taken and single or limited timepoints |
| Percentage of Participants With ssCavg ≥500 ng/mL of Serial PK (Subgroup 1) on Day 10 | Serial PK (Subgroup 1) on Day 10 at pre-dose, 1 hr. post start of infusion (SOI), end of infusion (EOI), 15 min. after EOI and 4, 8, 12, 24 hours post SOI | Characterization of the PK parameters of POS determined from plasma samples taken at steady-state after receiving IV administration of 300 mg POS twice a day (BID) on Day 1 and then 300 mg POS QD until at least Day 10. Steady-state Cavg, where Cavg is defined as AUC0-24hr divided by the dosing interval. The percentage of participants with ssCavg ≥500 ng/mL are presented. Subgroup 1 - Serial PK, multiple same-day blood draw, performed specifically for determination of PK parameters of Cavg, AUC, Cmin, Cmax, Tmax and Total Body Clearance in addition to plasma trough determination. Subgroup 2 - Sparse PK, once a day blood draw, performed for plasma trough determination only. |
| Steady-state Area Under the Concentration-time Curve (ssAUC0-24hr) of POS of Serial PK (Subgroup 1) on Day 10 | Serial PK (Subgroup 1) on Day 10 at pre-dose, 1 hr. post start of infusion (SOI), end of infusion (EOI), 15 min. after EOI and 4, 8, 12, 24 hours post SOI | Characterization of the PK parameters of POS determined from plasma samples taken at steady-state after receiving IV administration of 300 mg POS twice a day (BID) on Day 1 and then 300 mg POS QD until at least Day 10. AUC0-24 is defined as area under the plasma concentration-time curve from time 0 extrapolated to 24 hours. Subgroup 1 - Serial PK, multiple same-day blood draw, performed specifically for determination of PK parameters of Cavg, AUC, Cmin, Cmax, Tmax and Total Body Clearance in addition to plasma trough determination. Subgroup 2 - Sparse PK, once a day blood draw, performed for plasma trough determination only. |
| Steady State Maximum Concentration (ssCmax) of POS of Serial PK (Subgroup 1) on Day 10 | Serial PK (Subgroup 1) on Day 10 at pre-dose, 1 hr. post start of infusion (SOI), end of infusion (EOI), 15 min. after EOI and 4, 8, 12, 24 hours post SOI | Characterization of the PK parameters of POS determined from plasma samples taken at steady-state after receiving IV administration of 300 mg POS twice a day (BID) on Day 1 and then 300 mg POS QD until at least Day 10. Cmax is defined as the maximum concentration of POS in plasma. Subgroup 1 - Serial PK, multiple same-day blood draw, performed specifically for determination of PK parameters of Cavg, AUC, Cmin, Cmax, Tmax and Total Body Clearance in addition to plasma trough determination. Subgroup 2 - Sparse PK, once a day blood draw, performed for plasma trough determination only. |
| Steady State Minimum Concentration (ssCmin) of POS of Serial PK (Subgroup 1) on Day 10 | Serial PK (Subgroup 1) on Day 10 at pre-dose, 1 hr. post start of infusion (SOI), end of infusion (EOI), 15 min. after EOI and 4, 8, 12, 24 hours post SOI | Characterization of the PK parameters of POS determined from plasma samples taken at steady-state after receiving IV administration of 300 mg POS twice a day (BID) on Day 1 and then 300 mg POS QD until at least Day 10. Cmin is defined as the minimum concentration of POS in plasma. Subgroup 1 - Serial PK, multiple same-day blood draw, performed specifically for determination of PK parameters of Cavg, AUC, Cmin, Cmax, Tmax and Total Body Clearance in addition to plasma trough determination. Subgroup 2 - Sparse PK, once a day blood draw, performed for plasma trough determination only. |
| Time to Steady-state Maximum Concentration (ssTmax) of POS of Serial PK (Subgroup 1) on Day 10 | Serial PK (Subgroup 1) on Day 10 at pre-dose, 1 hr. post start of infusion (SOI), end of infusion (EOI), 15 min. after EOI and 4, 8, 12, 24 hours post SOI | Characterization of the PK parameters of POS determined from plasma samples taken at steady-state after receiving IV administration of 300 mg POS twice a day (BID) on Day 1 and then 300 mg POS QD until at least Day 10. Tmax is defined as the time it takes to achieve maximum concentration of POS in plasma. Subgroup 1 - Serial PK, multiple same-day blood draw, performed specifically for determination of PK parameters of Cavg, AUC, Cmin, Cmax, Tmax and Total Body Clearance in addition to plasma trough determination. Subgroup 2 - Sparse PK, once a day blood draw, performed for plasma trough determination only. |
| Total Body Clearance (CL) of POS of Serial PK (Subgroup 1) on Day 10 | Serial PK (Subgroup 1) on Day 10 at pre-dose, 1 hr. post start of infusion (SOI), end of infusion (EOI), 15 min. after EOI and 4, 8, 12, 24 hours post SOI | Characterization of the PK parameters of POS determined from plasma samples taken at steady-state after receiving IV administration of 300 mg POS twice a day (BID) on Day 1 and then 300 mg POS QD until at least Day 10. CL is defined as the time it takes for POS to be completely removed from the body's blood stream. Subgroup 1 - Serial PK, multiple same-day blood draw, performed specifically for determination of PK parameters of Cavg, AUC, Cmin, Cmax, Tmax and Total Body Clearance in addition to plasma trough determination. Subgroup 2 - Sparse PK, once a day blood draw, performed for plasma trough determination only. |
| Steady State (ss) Average Concentration (Cavg) of Posaconazole of Serial PK (Subgroup 1) on Day 10 | Serial PK (Subgroup 1) on Day 10 at pre-dose, 1 hr. post start of infusion (SOI), end of infusion (EOI), 15 min. after EOI and 4, 8, 12, 24 hours post SOI | Characterization of the pharmacokinetics (PK) parameters of POS determined from plasma samples taken at steady-state after receiving IV administration of 300 mg POS twice a day (BID) on Day 1 and then 300 mg POS QD until at least Day 10. Steady-state Cavg, where Cavg is defined as AUC0-24hr divided by the dosing interval. Subgroup 1 - Serial PK, multiple same-day blood draw, performed specifically for determination of PK parameters of Cavg, AUC, Cmin, Cmax, Tmax and Total Body Clearance in addition to plasma trough determination. Subgroup 2 - Sparse PK, once a day blood draw, performed for plasma trough determination only. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Discontinuations Due to an AE | Up to 28 days | Number of participants discontinued from study medication due to an AE where AEs are defined as any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. |
| Medically Significant Changes in Clinical Laboratory Results - Lab Values | Up to 28 days | The number of participants with clinical laboratory values outside of normal range |
| Medically Significant Changes in Clinical Laboratory Results - Vital Signs | Up to 28 days | The number of participants with values of vital signs outside of normal range |
| Survival Status | Up to 98 days | Survival assessment as to whether a participant is alive or dead, included all participants who died - 2 during study treatment, 1 during safety follow-up, 2 during survival follow-up (Day 60 to 70 post dose), and 1 participant who died during serious AE (SAE) follow-up at 97 days after first dose but was beyond the safety and the survival follow-up period |
| Participants With Invasive Fungal Infection (IFI) | Up to 28 days | Number of participants with possible, probable, or proven IFI observed during the whole study period |
| Adverse Events (AEs) | Up to 58 days | Number of participants with one or more AEs where AEs are defined as any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. |
Countries
China
Participant flow
Recruitment details
70 participants were randomized and 70 received at least one dose of study drug.
Participants by arm
| Arm | Count |
|---|---|
| Serial PK (Subgroup 1) Posaconazole (POS) 300 mg intravenous (IV) infusion twice on Day 1 followed by 300 mg IV infusion once daily on Days 2 to 10 (±1). At the discretion of the investigator, participants may have received POS 300 mg IV infusion once daily or 200 mg oral suspension 3 times daily for up to 18 additional days. Serial PK requires full intensive blood sampling for PK measurements | 30 |
| Sparse PK (Subgroup 2) POS 300 mg intravenous (IV) infusion twice on Day 1 followed by 300 mg IV infusion once daily on Days 2 to 10 (±1). At the discretion of the investigator, participants may have received POS 300 mg IV infusion once daily or 200 mg oral suspension 3 times daily for up to 18 additional days. Sparse PK requires sparse infrequent blood sampling for PK measurements | 40 |
| Total | 70 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 2 | 5 |
| Overall Study | Death | 1 | 2 |
| Overall Study | Physician Decision | 0 | 1 |
| Overall Study | Prohibited Drugs | 1 | 1 |
Baseline characteristics
| Characteristic | Sparse PK (Subgroup 2) | Total | Serial PK (Subgroup 1) |
|---|---|---|---|
| Age, Continuous 18 to 70 Years of Age | 45.4 Years STANDARD_DEVIATION 15.1 | 43 Years STANDARD_DEVIATION 14.5 | 39.8 Years STANDARD_DEVIATION 13.3 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 40 Participants | 70 Participants | 30 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 40 Participants | 70 Participants | 30 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Female | 20 Participants | 34 Participants | 14 Participants |
| Sex: Female, Male Male | 20 Participants | 36 Participants | 16 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 6 / 70 |
| other Total, other adverse events | 70 / 70 |
| serious Total, serious adverse events | 15 / 70 |
Outcome results
Primary
Percentage of Participants With ssCavg ≥500 ng/mL of Serial PK (Subgroup 1) on Day 10
Characterization of the PK parameters of POS determined from plasma samples taken at steady-state after receiving IV administration of 300 mg POS twice a day (BID) on Day 1 and then 300 mg POS QD until at least Day 10. Steady-state Cavg, where Cavg is defined as AUC0-24hr divided by the dosing interval. The percentage of participants with ssCavg ≥500 ng/mL are presented. Subgroup 1 - Serial PK, multiple same-day blood draw, performed specifically for determination of PK parameters of Cavg, AUC, Cmin, Cmax, Tmax and Total Body Clearance in addition to plasma trough determination. Subgroup 2 - Sparse PK, once a day blood draw, performed for plasma trough determination only.
Time frame: Serial PK (Subgroup 1) on Day 10 at pre-dose, 1 hr. post start of infusion (SOI), end of infusion (EOI), 15 min. after EOI and 4, 8, 12, 24 hours post SOI
Population: Analysis population includes participants who had serial blood draws on Day 10. Sparse PK (subgroup 2) is not included in this analysis because blood was drawn only once on Day 10 for plasma trough determination.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Serial PK (Subgroup 1) | Percentage of Participants With ssCavg ≥500 ng/mL of Serial PK (Subgroup 1) on Day 10 | Cavg 500 ng/mL to < 2500 ng/mL | 40.7 Percentage of Participants |
| Serial PK (Subgroup 1) | Percentage of Participants With ssCavg ≥500 ng/mL of Serial PK (Subgroup 1) on Day 10 | Cavg 2500 ng/ML to < 3650 ng/mL | 33.3 Percentage of Participants |
| Serial PK (Subgroup 1) | Percentage of Participants With ssCavg ≥500 ng/mL of Serial PK (Subgroup 1) on Day 10 | Cavg 3650 ng/mL or higher | 25.9 Percentage of Participants |
Primary
POS Plasma Trough Concentrations in the Serial PK and Sparse PK Subgroups
Pre-dose plasma trough concentrations by study day between serial PK and Sparse PK - where serial PK is defined as multiple serial blood sampling of more than 6 timepoints; and sparse PK is defined as few blood samples taken and single or limited timepoints
Time frame: Day 3, Day 6, Day 10, Day 15, Day 22, Day 28
Population: All evaluable participants in Subgroup 1 (Serial PK) and Subgroup 2 (Sparse PK) not yet switched to oral suspension.~Both groups received the same dose and drug administration and reflect only different blood sampling schedules.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Serial PK (Subgroup 1) | POS Plasma Trough Concentrations in the Serial PK and Sparse PK Subgroups | Day 15 | 2471.63 ng/mL | Standard Deviation 1495.2 |
| Serial PK (Subgroup 1) | POS Plasma Trough Concentrations in the Serial PK and Sparse PK Subgroups | Day 10 | 2473.78 ng/mL | Standard Deviation 1247.86 |
| Serial PK (Subgroup 1) | POS Plasma Trough Concentrations in the Serial PK and Sparse PK Subgroups | Day 6 | 2106.07 ng/mL | Standard Deviation 764.16 |
| Serial PK (Subgroup 1) | POS Plasma Trough Concentrations in the Serial PK and Sparse PK Subgroups | Day 3 | 1800.93 ng/mL | Standard Deviation 525.2 |
| Sparse PK (Subgroup 2) | POS Plasma Trough Concentrations in the Serial PK and Sparse PK Subgroups | Day 15 | 2680 ng/mL | Standard Deviation 1269 |
| Sparse PK (Subgroup 2) | POS Plasma Trough Concentrations in the Serial PK and Sparse PK Subgroups | Day 22 | 2603 ng/mL | Standard Deviation 1325 |
| Sparse PK (Subgroup 2) | POS Plasma Trough Concentrations in the Serial PK and Sparse PK Subgroups | Day 28 | 3180 ng/mL | Standard Deviation 1527 |
| Sparse PK (Subgroup 2) | POS Plasma Trough Concentrations in the Serial PK and Sparse PK Subgroups | Day 3 | 2033 ng/mL | Standard Deviation 650.9 |
| Sparse PK (Subgroup 2) | POS Plasma Trough Concentrations in the Serial PK and Sparse PK Subgroups | Day 6 | 2514 ng/mL | Standard Deviation 927.5 |
| Sparse PK (Subgroup 2) | POS Plasma Trough Concentrations in the Serial PK and Sparse PK Subgroups | Day 10 | 2466 ng/mL | Standard Deviation 1045 |
Primary
Steady-state Area Under the Concentration-time Curve (ssAUC0-24hr) of POS of Serial PK (Subgroup 1) on Day 10
Characterization of the PK parameters of POS determined from plasma samples taken at steady-state after receiving IV administration of 300 mg POS twice a day (BID) on Day 1 and then 300 mg POS QD until at least Day 10. AUC0-24 is defined as area under the plasma concentration-time curve from time 0 extrapolated to 24 hours. Subgroup 1 - Serial PK, multiple same-day blood draw, performed specifically for determination of PK parameters of Cavg, AUC, Cmin, Cmax, Tmax and Total Body Clearance in addition to plasma trough determination. Subgroup 2 - Sparse PK, once a day blood draw, performed for plasma trough determination only.
Time frame: Serial PK (Subgroup 1) on Day 10 at pre-dose, 1 hr. post start of infusion (SOI), end of infusion (EOI), 15 min. after EOI and 4, 8, 12, 24 hours post SOI
Population: Analysis population includes participants who had serial blood draws on Day 10. Sparse PK (subgroup 2) is not included in this analysis because blood was drawn only once on Day 10 for plasma trough determination.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Serial PK (Subgroup 1) | Steady-state Area Under the Concentration-time Curve (ssAUC0-24hr) of POS of Serial PK (Subgroup 1) on Day 10 | 71670.8 hr*ng/mL | Standard Deviation 25788.11 |
Primary
Steady State Maximum Concentration (ssCmax) of POS of Serial PK (Subgroup 1) on Day 10
Characterization of the PK parameters of POS determined from plasma samples taken at steady-state after receiving IV administration of 300 mg POS twice a day (BID) on Day 1 and then 300 mg POS QD until at least Day 10. Cmax is defined as the maximum concentration of POS in plasma. Subgroup 1 - Serial PK, multiple same-day blood draw, performed specifically for determination of PK parameters of Cavg, AUC, Cmin, Cmax, Tmax and Total Body Clearance in addition to plasma trough determination. Subgroup 2 - Sparse PK, once a day blood draw, performed for plasma trough determination only.
Time frame: Serial PK (Subgroup 1) on Day 10 at pre-dose, 1 hr. post start of infusion (SOI), end of infusion (EOI), 15 min. after EOI and 4, 8, 12, 24 hours post SOI
Population: Analysis population includes participants who had serial blood draws on Day 10. Sparse PK (subgroup 2) is not included in this analysis because blood was drawn only once on Day 10 for plasma trough determination.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Serial PK (Subgroup 1) | Steady State Maximum Concentration (ssCmax) of POS of Serial PK (Subgroup 1) on Day 10 | 4612.22 ng/mL | Standard Deviation 1221.68 |
Primary
Steady State Minimum Concentration (ssCmin) of POS of Serial PK (Subgroup 1) on Day 10
Characterization of the PK parameters of POS determined from plasma samples taken at steady-state after receiving IV administration of 300 mg POS twice a day (BID) on Day 1 and then 300 mg POS QD until at least Day 10. Cmin is defined as the minimum concentration of POS in plasma. Subgroup 1 - Serial PK, multiple same-day blood draw, performed specifically for determination of PK parameters of Cavg, AUC, Cmin, Cmax, Tmax and Total Body Clearance in addition to plasma trough determination. Subgroup 2 - Sparse PK, once a day blood draw, performed for plasma trough determination only.
Time frame: Serial PK (Subgroup 1) on Day 10 at pre-dose, 1 hr. post start of infusion (SOI), end of infusion (EOI), 15 min. after EOI and 4, 8, 12, 24 hours post SOI
Population: Analysis population includes participants who had serial blood draws on Day 10. Sparse PK (subgroup 2) is not included in this analysis because blood was drawn only once on Day 10 for plasma trough determination.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Serial PK (Subgroup 1) | Steady State Minimum Concentration (ssCmin) of POS of Serial PK (Subgroup 1) on Day 10 | 2311.33 ng/mL | Standard Deviation 1119.28 |
Primary
Steady State (ss) Average Concentration (Cavg) of Posaconazole of Serial PK (Subgroup 1) on Day 10
Characterization of the pharmacokinetics (PK) parameters of POS determined from plasma samples taken at steady-state after receiving IV administration of 300 mg POS twice a day (BID) on Day 1 and then 300 mg POS QD until at least Day 10. Steady-state Cavg, where Cavg is defined as AUC0-24hr divided by the dosing interval. Subgroup 1 - Serial PK, multiple same-day blood draw, performed specifically for determination of PK parameters of Cavg, AUC, Cmin, Cmax, Tmax and Total Body Clearance in addition to plasma trough determination. Subgroup 2 - Sparse PK, once a day blood draw, performed for plasma trough determination only.
Time frame: Serial PK (Subgroup 1) on Day 10 at pre-dose, 1 hr. post start of infusion (SOI), end of infusion (EOI), 15 min. after EOI and 4, 8, 12, 24 hours post SOI
Population: Analysis population includes participants who had serial blood draws on Day 10. Sparse PK (subgroup 2) is not included in this analysis because blood was drawn only once on Day 10 for plasma trough determination.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Serial PK (Subgroup 1) | Steady State (ss) Average Concentration (Cavg) of Posaconazole of Serial PK (Subgroup 1) on Day 10 | 2986.28 ng/mL | Standard Deviation 1074.5 |
Primary
Time to Steady-state Maximum Concentration (ssTmax) of POS of Serial PK (Subgroup 1) on Day 10
Characterization of the PK parameters of POS determined from plasma samples taken at steady-state after receiving IV administration of 300 mg POS twice a day (BID) on Day 1 and then 300 mg POS QD until at least Day 10. Tmax is defined as the time it takes to achieve maximum concentration of POS in plasma. Subgroup 1 - Serial PK, multiple same-day blood draw, performed specifically for determination of PK parameters of Cavg, AUC, Cmin, Cmax, Tmax and Total Body Clearance in addition to plasma trough determination. Subgroup 2 - Sparse PK, once a day blood draw, performed for plasma trough determination only.
Time frame: Serial PK (Subgroup 1) on Day 10 at pre-dose, 1 hr. post start of infusion (SOI), end of infusion (EOI), 15 min. after EOI and 4, 8, 12, 24 hours post SOI
Population: Analysis population includes participants who had serial blood draws on Day 10. Sparse PK (subgroup 2) is not included in this analysis because blood was drawn only once on Day 10 for plasma trough determination.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Serial PK (Subgroup 1) | Time to Steady-state Maximum Concentration (ssTmax) of POS of Serial PK (Subgroup 1) on Day 10 | 1.63 hr | Standard Deviation 0.23 |
Primary
Total Body Clearance (CL) of POS of Serial PK (Subgroup 1) on Day 10
Characterization of the PK parameters of POS determined from plasma samples taken at steady-state after receiving IV administration of 300 mg POS twice a day (BID) on Day 1 and then 300 mg POS QD until at least Day 10. CL is defined as the time it takes for POS to be completely removed from the body's blood stream. Subgroup 1 - Serial PK, multiple same-day blood draw, performed specifically for determination of PK parameters of Cavg, AUC, Cmin, Cmax, Tmax and Total Body Clearance in addition to plasma trough determination. Subgroup 2 - Sparse PK, once a day blood draw, performed for plasma trough determination only.
Time frame: Serial PK (Subgroup 1) on Day 10 at pre-dose, 1 hr. post start of infusion (SOI), end of infusion (EOI), 15 min. after EOI and 4, 8, 12, 24 hours post SOI
Population: Analysis population includes participants who had serial blood draws on Day 10. Sparse PK (subgroup 2) is not included in this analysis because blood was drawn only once on Day 10 for plasma trough determination.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Serial PK (Subgroup 1) | Total Body Clearance (CL) of POS of Serial PK (Subgroup 1) on Day 10 | 4767.90 mL/hr | Standard Deviation 1805.24 |
Secondary
Adverse Events (AEs)
Number of participants with one or more AEs where AEs are defined as any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention.
Time frame: Up to 58 days
Population: All participants who received at least one dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Serial PK (Subgroup 1) | Adverse Events (AEs) | 70 Number of Participants |
Secondary
Discontinuations Due to an AE
Number of participants discontinued from study medication due to an AE where AEs are defined as any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention.
Time frame: Up to 28 days
Population: All participants who received at least one dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Serial PK (Subgroup 1) | Discontinuations Due to an AE | 9 Participants |
Secondary
Medically Significant Changes in Clinical Laboratory Results - Lab Values
The number of participants with clinical laboratory values outside of normal range
Time frame: Up to 28 days
Population: All evaluable participants in Subgroup 1 (Serial PK) and Subgroup 2 (Sparse PK) not yet switched to oral suspension. Both groups received the same dose and drug administration and reflect only different blood sampling schedules.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Serial PK (Subgroup 1) | Medically Significant Changes in Clinical Laboratory Results - Lab Values | 30 Participants |
| Sparse PK (Subgroup 2) | Medically Significant Changes in Clinical Laboratory Results - Lab Values | 35 Participants |
Secondary
Medically Significant Changes in Clinical Laboratory Results - Vital Signs
The number of participants with values of vital signs outside of normal range
Time frame: Up to 28 days
Population: All evaluable participants in Subgroup 1 (Serial PK) and Subgroup 2 (Sparse PK) not yet switched to oral suspension. Both groups received the same dose and drug administration and reflect only different blood sampling schedules.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Serial PK (Subgroup 1) | Medically Significant Changes in Clinical Laboratory Results - Vital Signs | 27 Participants |
| Sparse PK (Subgroup 2) | Medically Significant Changes in Clinical Laboratory Results - Vital Signs | 31 Participants |
Secondary
Participants With Invasive Fungal Infection (IFI)
Number of participants with possible, probable, or proven IFI observed during the whole study period
Time frame: Up to 28 days
Population: All participants who received at least one dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Serial PK (Subgroup 1) | Participants With Invasive Fungal Infection (IFI) | 2 Participants |
Secondary
Survival Status
Survival assessment as to whether a participant is alive or dead, included all participants who died - 2 during study treatment, 1 during safety follow-up, 2 during survival follow-up (Day 60 to 70 post dose), and 1 participant who died during serious AE (SAE) follow-up at 97 days after first dose but was beyond the safety and the survival follow-up period
Time frame: Up to 98 days
Population: All participants who received at least one dose of study drug.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Serial PK (Subgroup 1) | Survival Status | Alive | 64 Participants |
| Serial PK (Subgroup 1) | Survival Status | Dead | 6 Participants |