Fungal Infection
Conditions
Keywords
Antifungal Agents pharmacokinetics, Mycoses prevention and control
Brief summary
The purpose of this study is to collect pharmacokinetic (PK) information related to how well intravenous Posaconazole (POS IV), is distributed in the body and to determine the safety and tolerability of this new formulation. In addition, the PK, safety, and tolerability of switching from taking POS IV to taking Posaconazole Oral Suspension (POS Oral) will be evaluated. The data collected in this study will be compared to data collected in previous studies. Individuals who have been diagnosed by their physicians with a blood disease or cancer that can affect their infection-fighting white blood cells will be asked to participate in the trial. Since these blood diseases and their treatments can weaken the immune system, they may put these individuals at a high risk for getting a serious fungal infection of their internal organs or blood (invasive fungal infection). As these fungal infections can be hard to detect early and can be life-threatening, many physicians believe that individuals diagnosed with these diseases should receive antifungal therapy to try to lower their risk of getting this type of infection. Enrollment into this study will take place in several stages (cohorts). The determination of which cohort an individual will be asked to participate in is based on which cohort is open at the site at the time the individual is approached to consider study participation.
Interventions
DRUGPosaconazole
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
PREVENTION
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Adult subjects greater than or equal to 18 years of age (weighing greater than 34 kg \[75 lb\]), of either sex and of any race/ethnicity. * Disease definition for each subject: Anticipated (likely to develop within 3 days to 5 days) or documented prolonged neutropenia (absolute neutrophil count \[ANC\] \<500/mm\^3 \[0.5 x 10\^9/L\]) at Baseline 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) or chronic myelogenous leukemia in blast crisis * Disease definition for each Cohort 3 subject: In addition to subjects defined above, allogeneic hematopoietic stem cell transplant (HSCT) subjects may be randomized in either the pre-engraftment period (i.e., after they have received their conditioning regimen for the transplant, but while they are still neutropenic) or in the post-engraftment period if they are receiving immunosuppressive therapy for prevention or treatment of graft-versus-host disease (e.g., steroids, tacrolimus, cyclosporin, mycophenolate mofetil, and antithymocyte globulin).
Exclusion criteria
* A female subject must not be pregnant, must not intend to become pregnant during the study, or must not be nursing. * Excluded prior treatments. A subject must not have received systemic antifungal therapy (oral, intravenous, or inhaled) for the treatment of proven or probable IFI within 30 days of Enrollment. * A subject must not have moderate or severe liver dysfunction at Baseline, defined as aspartate aminotransferase (AST) or alanine aminotransferase (ALT) levels greater than three times the upper limit of normal (ULN), AND a total bilirubin level greater than two times the ULN. For Cohorts 1 and 2, a subject must not have a known or suspected history of Gilbert's disease. * A subject must not have an electrocardiogram (ECG) with a prolonged QTc interval by manual reading: QTc greater than 500 msec. * A subject must not have prior enrollment in this study, or other POS studies within 90 days of study entry. * A subject must not have a known or suspected invasive or systemic fungal infection at Baseline. Those subjects receiving empiric anti-fungal therapy within 7 days prior to Baseline must have had a diagnostic work-up that ruled out a possible invasive fungal infection. * A subject must not have creatinine clearance levels (measured or calculated) below 50 mL/min. * A subject must not have a history of Type I hypersensitivity or idiosyncratic reactions to azole agents.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Single Dose Trough Concentration of IV Posaconazole (Cmin) | 12 hours after start of infusion on Day 1 (Cohorts 0, 1 and 2) | Blood samples were collected from participants for the determination of plasma POS concentration. |
| Steady State Trough Concentration of IV Posaconazole (Cmin) | 24 hours after start of infusion on Day 14 (Cohorts 1 and 2), or Day 10 (Cohort 3) | Blood samples were collected from participants for the determination of plasma POS concentration. |
| Single Dose Maximum Concentration of IV Posaconazole (Cmax) | Predose and 1, 1.5, 1.75, 4, 8, and 12 hours after start of infusion on Day 1 (Cohorts 0, 1 and 2) | Blood samples were collected from participants for the determination of plasma POS concentration. |
| Steady State Maximum Concentration of IV Posaconazole (Cmax) | Predose and 1, 1.5, 1.75, 4, 8, and 12 hours after start of infusion on Day 14 (Cohorts 1 and 2), or Day 10 (Cohort 3) | Blood samples were collected from participants for the determination of plasma POS concentration. |
| Single Dose Time of Observed Maximum Concentration of IV Posaconazole (Tmax) | Predose and 1, 1.5, 1.75, 4, 8, and 12 hours after start of infusion on Day 1 (Cohorts 0 and 1) | Blood samples were collected from participants for the determination of plasma POS concentration. |
| Steady State Time of Observed Maximum Concentration of IV Posaconazole (Tmax) | Predose and 1, 1.5, 1.75, 4, 8, and 12 hours after start of infusion on Day 14 (Cohorts 1 and 2), or Day 10 (Cohort 3) | Blood samples were collected from participants for the determination of plasma POS concentration. |
| Single Dose Area Under the Concentration Versus Time Curve of IV Posaconazole (AUC) | Predose and 1, 1.5, 1.75, 4, 8, and 12 hours after start of infusion on Day 1 (Cohorts 0, 1 and 2) | Blood samples were collected from participants for the determination of plasma POS concentration. |
| Steady State Area Under the Concentration Versus Time Curve of IV Posaconazole (AUC) | Predose and 1, 1.5, 1.75, 4, 8, 12, and 24 hours after start of infusion on Day 14 (Cohorts 1 and 2), or Day 10 (Cohort 3) | Blood samples were collected from participants for the determination of plasma POS concentration. |
| Steady State Average Concentration of IV Posaconazole (Cavg) | Predose and 1, 1.5, 1.75, 4, 8, 12, and 24 hours after start of infusion on Day 14 (Cohorts 1 and 2), or Day 10 (Cohort 3) | Blood samples were collected from participants for the determination of plasma POS concentration. Cavg was calculated as steady state AUC / dosing interval (24 hours). |
| Steady State Total Body Clearance of IV Posaconazole (CL) | Predose and 1, 1.5, 1.75, 4, 8, and 12 hours after start of infusion on Day 14 (Cohorts 1 and 2), or Day 10 (Cohort 3) | Blood samples were collected from participants for the determination of plasma POS concentration. |
| Steady State Trough Concentration of Oral Posaconazole (Cmin) | 12 hours after dosing on Day 7 (Cohort 0), or Day 28 (Cohorts 1 and 2) | Blood samples were collected from participants for the determination of plasma POS concentration. |
| Steady State Maximum Concentration of Oral Posaconazole (Cmax) | Predose and 3, 5, 8 and 12 hours after dosing on Day 7 (Cohort 0), or Day 28 (Cohorts 1 and 2) | Blood samples were collected from participants for the determination of plasma POS concentration. |
| Steady State Time of Observed Maximum Concentration of Oral Posaconazole (Tmax) | Predose and 3, 5, 8 and 12 hours after dosing on Day 7 (Cohort 0), or Day 28 (Cohorts 1 and 2) | Blood samples were collected from participants for the determination of plasma POS concentration. |
| Steady State Area Under the Concentration Versus Time Curve of Oral Posaconazole (AUC) | Predose and 3, 5, 8 and 12 hours after dosing on Day 7 (Cohort 0), or Day 28 (Cohorts 1 and 2) | Blood samples were collected from participants for the determination of plasma POS concentration. |
| Steady State Average Concentration of Oral Posaconazole (Cavg) | Predose and 3, 5, 8 and 12 hours after dosing on Day 7 (Cohort 0), or Day 28 (Cohorts 1 and 2) | Blood samples were collected from participants for the determination of plasma POS concentration. Cavg was calculated as steady state AUC / dosing interval (12 hours). |
| Steady State Apparent Total Body Clearance of Oral Posaconazole (CL/F) | Predose and 3, 5, 8 and 12 hours after dosing on Day 7 (Cohort 0), or Day 28 (Cohorts 1 and 2) | Blood samples were collected from participants for the determination of plasma POS concentration. |
Participant flow
Pre-assignment details
All participants who started the study were eligible to enter the follow-up phase, whether or not they completed the treatment phase.
Participants by arm
| Arm | Count |
|---|---|
| POS 200 mg IV Single Dose (Cohort 0) POS 200 mg IV single dose on Day 1 followed 12 hours later by POS oral 400 mg, then by POS oral 400 mg BID on Days 2 through 6 and a single morning dose on Day 7 (Cohort 0) | 10 |
| Placebo IV Single Dose (Cohort 0) Placebo IV single dose on Day 1, followed 12 hours later by POS oral 400 mg, then by POS oral 400 mg BID on Days 2 through 6 and a single morning dose on Day 7 (Cohort 0) | 11 |
| POS 200 mg IV BID (Cohort 1) POS 200 mg IV BID on Day 1, followed by POS 200 mg IV once daily on Days 2 through 14, then by POS 400 mg oral BID through Day 28 (Cohort 1) | 21 |
| POS 300 mg IV BID (Cohort 2) POS 300 mg IV BID on Day 1, followed by POS 300 mg IV once daily on Days 2 through 14, then by POS 400 mg oral BID through Day 28 (Cohort 2). After Day 5, POS IV was administered continuously or intermittently, depending on oral tolerability. | 24 |
| POS 300 mg IV BID (Cohort 3) POS 300 mg IV BID on Day 1 followed by POS 300 mg IV once daily on Days 2 through 5, then by POS 200 mg oral TID or POS 400 mg oral BID through Day 28 or POS 200-300 mg IV once daily as required (Cohort 3). After Day 5, POS IV was administered continuously or intermittently, depending on oral tolerability. | 213 |
| Total | 279 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Follow-up Phase | Administrative | 0 | 0 | 0 | 0 | 1 |
| Follow-up Phase | Adverse Event | 0 | 0 | 0 | 2 | 27 |
| Follow-up Phase | Progression of disease | 0 | 0 | 0 | 0 | 2 |
| Follow-up Phase | Protocol Violation | 0 | 0 | 1 | 0 | 3 |
| Follow-up Phase | Treatment failure | 0 | 0 | 0 | 0 | 4 |
| Follow-up Phase | Withdrawal by Subject | 0 | 0 | 0 | 0 | 10 |
| Treatment Phase | Adverse Event | 0 | 1 | 3 | 7 | 35 |
| Treatment Phase | Progression of disease | 0 | 0 | 0 | 0 | 2 |
| Treatment Phase | Protocol Violation | 0 | 0 | 1 | 0 | 3 |
| Treatment Phase | Treatment Failure | 0 | 0 | 1 | 0 | 5 |
| Treatment Phase | Withdrawal by Subject | 0 | 0 | 2 | 0 | 15 |
Baseline characteristics
| Characteristic | POS 200 mg IV Single Dose (Cohort 0) | Placebo IV Single Dose (Cohort 0) | POS 200 mg IV BID (Cohort 1) | POS 300 mg IV BID (Cohort 2) | POS 300 mg IV BID (Cohort 3) | Total |
|---|---|---|---|---|---|---|
| Age, Continuous | 56.8 Years STANDARD_DEVIATION 17.4 | 59.5 Years STANDARD_DEVIATION 12.3 | 49.1 Years STANDARD_DEVIATION 14.7 | 52.4 Years STANDARD_DEVIATION 13.4 | 50.7 Years STANDARD_DEVIATION 14.7 | 51.3 Years STANDARD_DEVIATION 14.7 |
| Sex: Female, Male Female | 5 Participants | 6 Participants | 8 Participants | 11 Participants | 96 Participants | 126 Participants |
| Sex: Female, Male Male | 5 Participants | 5 Participants | 13 Participants | 13 Participants | 117 Participants | 153 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 10 / 10 | 11 / 11 | 20 / 21 | 229 / 237 |
| serious Total, serious adverse events | 2 / 10 | 2 / 11 | 4 / 21 | 71 / 237 |
Outcome results
Primary
Single Dose Area Under the Concentration Versus Time Curve of IV Posaconazole (AUC)
Blood samples were collected from participants for the determination of plasma POS concentration.
Time frame: Predose and 1, 1.5, 1.75, 4, 8, and 12 hours after start of infusion on Day 1 (Cohorts 0, 1 and 2)
Population: The PK-evaluable population included participants who had no major protocol violations and had documented adherence to the dosing and PK regimens. Cohort 3 was not evaluated for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| POS 200 mg IV Single Dose (Cohort 0) | Single Dose Area Under the Concentration Versus Time Curve of IV Posaconazole (AUC) | 5940 hour*ng/mL | Standard Deviation 2190 |
| POS 200 mg IV BID (Cohort 1) | Single Dose Area Under the Concentration Versus Time Curve of IV Posaconazole (AUC) | 5390 hour*ng/mL | Standard Deviation 1540 |
| POS 300 mg IV BID (Cohort 2) | Single Dose Area Under the Concentration Versus Time Curve of IV Posaconazole (AUC) | 8240 hour*ng/mL | Standard Deviation 2140 |
Primary
Single Dose Maximum Concentration of IV Posaconazole (Cmax)
Blood samples were collected from participants for the determination of plasma POS concentration.
Time frame: Predose and 1, 1.5, 1.75, 4, 8, and 12 hours after start of infusion on Day 1 (Cohorts 0, 1 and 2)
Population: The PK-evaluable population included participants who had no major protocol violations and had documented adherence to the dosing and PK regimens. Cohort 3 was not evaluated for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| POS 200 mg IV Single Dose (Cohort 0) | Single Dose Maximum Concentration of IV Posaconazole (Cmax) | 881 ng/mL | Standard Deviation 334 |
| POS 200 mg IV BID (Cohort 1) | Single Dose Maximum Concentration of IV Posaconazole (Cmax) | 990 ng/mL | Standard Deviation 467 |
| POS 300 mg IV BID (Cohort 2) | Single Dose Maximum Concentration of IV Posaconazole (Cmax) | 1590 ng/mL | Standard Deviation 980 |
Primary
Single Dose Time of Observed Maximum Concentration of IV Posaconazole (Tmax)
Blood samples were collected from participants for the determination of plasma POS concentration.
Time frame: Predose and 1, 1.5, 1.75, 4, 8, and 12 hours after start of infusion on Day 1 (Cohorts 0 and 1)
Population: The PK-evaluable population included participants who had no major protocol violations and had documented adherence to the dosing and PK regimens. Cohort 3 was not evaluated for this outcome measure.
| Arm | Measure | Value (MEDIAN) | Dispersion |
|---|---|---|---|
| POS 200 mg IV Single Dose (Cohort 0) | Single Dose Time of Observed Maximum Concentration of IV Posaconazole (Tmax) | 1.42 Hours | — |
| POS 200 mg IV BID (Cohort 1) | Single Dose Time of Observed Maximum Concentration of IV Posaconazole (Tmax) | 1.48 Hours | Full Range 50 |
| POS 300 mg IV BID (Cohort 2) | Single Dose Time of Observed Maximum Concentration of IV Posaconazole (Tmax) | 1.54 Hours | — |
Primary
Single Dose Trough Concentration of IV Posaconazole (Cmin)
Blood samples were collected from participants for the determination of plasma POS concentration.
Time frame: 12 hours after start of infusion on Day 1 (Cohorts 0, 1 and 2)
Population: The PK-evaluable population included participants who had no major protocol violations and had documented adherence to the dosing and PK regimens. Cohort 3 was not evaluated for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| POS 200 mg IV Single Dose (Cohort 0) | Single Dose Trough Concentration of IV Posaconazole (Cmin) | 318 ng/mL | Standard Deviation 107 |
| POS 200 mg IV BID (Cohort 1) | Single Dose Trough Concentration of IV Posaconazole (Cmin) | 295 ng/mL | Standard Deviation 113 |
| POS 300 mg IV BID (Cohort 2) | Single Dose Trough Concentration of IV Posaconazole (Cmin) | 467 ng/mL | Standard Deviation 172 |
Primary
Steady State Apparent Total Body Clearance of Oral Posaconazole (CL/F)
Blood samples were collected from participants for the determination of plasma POS concentration.
Time frame: Predose and 3, 5, 8 and 12 hours after dosing on Day 7 (Cohort 0), or Day 28 (Cohorts 1 and 2)
Population: CL/F for posaconazole was not calculated in this study because it was collected in other studies more appropriate for evaluation of this parameter
Primary
Steady State Area Under the Concentration Versus Time Curve of IV Posaconazole (AUC)
Blood samples were collected from participants for the determination of plasma POS concentration.
Time frame: Predose and 1, 1.5, 1.75, 4, 8, 12, and 24 hours after start of infusion on Day 14 (Cohorts 1 and 2), or Day 10 (Cohort 3)
Population: The PK-evaluable population included participants who had no major protocol violations and had documented adherence to the dosing and PK regimens.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| POS 200 mg IV Single Dose (Cohort 0) | Steady State Area Under the Concentration Versus Time Curve of IV Posaconazole (AUC) | 28241 hour*ng/mL | Standard Deviation 14511 |
| POS 200 mg IV BID (Cohort 1) | Steady State Area Under the Concentration Versus Time Curve of IV Posaconazole (AUC) | 33754 hour*ng/mL | Standard Deviation 14196 |
| POS 300 mg IV BID (Cohort 2) | Steady State Area Under the Concentration Versus Time Curve of IV Posaconazole (AUC) | 37586 hour*ng/mL | Standard Deviation 11504 |
Primary
Steady State Area Under the Concentration Versus Time Curve of Oral Posaconazole (AUC)
Blood samples were collected from participants for the determination of plasma POS concentration.
Time frame: Predose and 3, 5, 8 and 12 hours after dosing on Day 7 (Cohort 0), or Day 28 (Cohorts 1 and 2)
Population: The PK-evaluable population included participants who had no major protocol violations and had documented adherence to the dosing and PK regimens. Cohort 3 was not evaluated for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| POS 200 mg IV Single Dose (Cohort 0) | Steady State Area Under the Concentration Versus Time Curve of Oral Posaconazole (AUC) | 5080 hour*ng/mL | Standard Deviation 1700 |
| POS 200 mg IV BID (Cohort 1) | Steady State Area Under the Concentration Versus Time Curve of Oral Posaconazole (AUC) | 6920 hour*ng/mL | Standard Deviation 1910 |
| POS 300 mg IV BID (Cohort 2) | Steady State Area Under the Concentration Versus Time Curve of Oral Posaconazole (AUC) | 3970 hour*ng/mL | Standard Deviation 2050 |
Primary
Steady State Average Concentration of IV Posaconazole (Cavg)
Blood samples were collected from participants for the determination of plasma POS concentration. Cavg was calculated as steady state AUC / dosing interval (24 hours).
Time frame: Predose and 1, 1.5, 1.75, 4, 8, 12, and 24 hours after start of infusion on Day 14 (Cohorts 1 and 2), or Day 10 (Cohort 3)
Population: The PK-evaluable population included participants who had no major protocol violations and had documented adherence to the dosing and PK regimens.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| POS 200 mg IV Single Dose (Cohort 0) | Steady State Average Concentration of IV Posaconazole (Cavg) | 1180 ng/mL | Standard Deviation 605 |
| POS 200 mg IV BID (Cohort 1) | Steady State Average Concentration of IV Posaconazole (Cavg) | 1410 ng/mL | Standard Deviation 592 |
| POS 300 mg IV BID (Cohort 2) | Steady State Average Concentration of IV Posaconazole (Cavg) | 1566 ng/mL | Standard Deviation 479 |
Primary
Steady State Average Concentration of Oral Posaconazole (Cavg)
Blood samples were collected from participants for the determination of plasma POS concentration. Cavg was calculated as steady state AUC / dosing interval (12 hours).
Time frame: Predose and 3, 5, 8 and 12 hours after dosing on Day 7 (Cohort 0), or Day 28 (Cohorts 1 and 2)
Population: The PK-evaluable population included participants who had no major protocol violations and had documented adherence to the dosing and PK regimens. Cohort 3 was not evaluated for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| POS 200 mg IV Single Dose (Cohort 0) | Steady State Average Concentration of Oral Posaconazole (Cavg) | 423 ng/mL | Standard Deviation 144 |
| POS 200 mg IV BID (Cohort 1) | Steady State Average Concentration of Oral Posaconazole (Cavg) | 570 ng/mL | Standard Deviation 160 |
| POS 300 mg IV BID (Cohort 2) | Steady State Average Concentration of Oral Posaconazole (Cavg) | 331 ng/mL | Standard Deviation 172 |
Primary
Steady State Maximum Concentration of IV Posaconazole (Cmax)
Blood samples were collected from participants for the determination of plasma POS concentration.
Time frame: Predose and 1, 1.5, 1.75, 4, 8, and 12 hours after start of infusion on Day 14 (Cohorts 1 and 2), or Day 10 (Cohort 3)
Population: The PK-evaluable population included participants who had no major protocol violations and had documented adherence to the dosing and PK regimens.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| POS 200 mg IV Single Dose (Cohort 0) | Steady State Maximum Concentration of IV Posaconazole (Cmax) | 1947 ng/mL | Standard Deviation 966 |
| POS 200 mg IV BID (Cohort 1) | Steady State Maximum Concentration of IV Posaconazole (Cmax) | 2610 ng/mL | Standard Deviation 1010 |
| POS 300 mg IV BID (Cohort 2) | Steady State Maximum Concentration of IV Posaconazole (Cmax) | 3696 ng/mL | Standard Deviation 2950 |
Primary
Steady State Maximum Concentration of Oral Posaconazole (Cmax)
Blood samples were collected from participants for the determination of plasma POS concentration.
Time frame: Predose and 3, 5, 8 and 12 hours after dosing on Day 7 (Cohort 0), or Day 28 (Cohorts 1 and 2)
Population: The PK-evaluable population included participants who had no major protocol violations and had documented adherence to the dosing and PK regimens. Cohort 3 was not evaluated for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| POS 200 mg IV Single Dose (Cohort 0) | Steady State Maximum Concentration of Oral Posaconazole (Cmax) | 494 ng/mL | Standard Deviation 176 |
| POS 200 mg IV BID (Cohort 1) | Steady State Maximum Concentration of Oral Posaconazole (Cmax) | 811 ng/mL | Standard Deviation 208 |
| POS 300 mg IV BID (Cohort 2) | Steady State Maximum Concentration of Oral Posaconazole (Cmax) | 430 ng/mL | Standard Deviation 260 |
Primary
Steady State Time of Observed Maximum Concentration of IV Posaconazole (Tmax)
Blood samples were collected from participants for the determination of plasma POS concentration.
Time frame: Predose and 1, 1.5, 1.75, 4, 8, and 12 hours after start of infusion on Day 14 (Cohorts 1 and 2), or Day 10 (Cohort 3)
Population: The PK-evaluable population included participants who had no major protocol violations and had documented adherence to the dosing and PK regimens.
| Arm | Measure | Value (MEDIAN) | Dispersion |
|---|---|---|---|
| POS 200 mg IV Single Dose (Cohort 0) | Steady State Time of Observed Maximum Concentration of IV Posaconazole (Tmax) | 1.00 Hours | Full Range 50 |
| POS 200 mg IV BID (Cohort 1) | Steady State Time of Observed Maximum Concentration of IV Posaconazole (Tmax) | 1.50 Hours | Full Range 39 |
| POS 300 mg IV BID (Cohort 2) | Steady State Time of Observed Maximum Concentration of IV Posaconazole (Tmax) | 1.52 Hours | Full Range 80 |
Primary
Steady State Time of Observed Maximum Concentration of Oral Posaconazole (Tmax)
Blood samples were collected from participants for the determination of plasma POS concentration.
Time frame: Predose and 3, 5, 8 and 12 hours after dosing on Day 7 (Cohort 0), or Day 28 (Cohorts 1 and 2)
Population: The PK-evaluable population included participants who had no major protocol violations and had documented adherence to the dosing and PK regimens. Cohort 3 was not evaluated for this outcome measure.
| Arm | Measure | Value (MEDIAN) | Dispersion |
|---|---|---|---|
| POS 200 mg IV Single Dose (Cohort 0) | Steady State Time of Observed Maximum Concentration of Oral Posaconazole (Tmax) | 3.03 Hours | — |
| POS 200 mg IV BID (Cohort 1) | Steady State Time of Observed Maximum Concentration of Oral Posaconazole (Tmax) | 3.05 Hours | Full Range 50 |
| POS 300 mg IV BID (Cohort 2) | Steady State Time of Observed Maximum Concentration of Oral Posaconazole (Tmax) | 5.54 Hours | Full Range 39 |
Primary
Steady State Total Body Clearance of IV Posaconazole (CL)
Blood samples were collected from participants for the determination of plasma POS concentration.
Time frame: Predose and 1, 1.5, 1.75, 4, 8, and 12 hours after start of infusion on Day 14 (Cohorts 1 and 2), or Day 10 (Cohort 3)
Population: CL for posaconazole was not calculated in this study because it was collected in other studies more appropriate for evaluation of this parameter.
Primary
Steady State Trough Concentration of IV Posaconazole (Cmin)
Blood samples were collected from participants for the determination of plasma POS concentration.
Time frame: 24 hours after start of infusion on Day 14 (Cohorts 1 and 2), or Day 10 (Cohort 3)
Population: The PK-evaluable population included participants who had no major protocol violations and had documented adherence to the dosing and PK regimens.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| POS 200 mg IV Single Dose (Cohort 0) | Steady State Trough Concentration of IV Posaconazole (Cmin) | 958 ng/mL | Standard Deviation 605 |
| POS 200 mg IV BID (Cohort 1) | Steady State Trough Concentration of IV Posaconazole (Cmin) | 1046 ng/mL | Standard Deviation 515 |
| POS 300 mg IV BID (Cohort 2) | Steady State Trough Concentration of IV Posaconazole (Cmin) | 1164 ng/mL | Standard Deviation 462 |
Primary
Steady State Trough Concentration of Oral Posaconazole (Cmin)
Blood samples were collected from participants for the determination of plasma POS concentration.
Time frame: 12 hours after dosing on Day 7 (Cohort 0), or Day 28 (Cohorts 1 and 2)
Population: The PK-evaluable population included participants who had no major protocol violations and had documented adherence to the dosing and PK regimens. Cohort 3 was not evaluated for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| POS 200 mg IV Single Dose (Cohort 0) | Steady State Trough Concentration of Oral Posaconazole (Cmin) | 370 ng/mL | Standard Deviation 125 |
| POS 200 mg IV BID (Cohort 1) | Steady State Trough Concentration of Oral Posaconazole (Cmin) | 532 ng/mL | Standard Deviation 266 |
| POS 300 mg IV BID (Cohort 2) | Steady State Trough Concentration of Oral Posaconazole (Cmin) | 316 ng/mL | Standard Deviation 164 |