Pharmacokinetics and Safety of Intravenous Posaconazole (MK-5592) in Chinese Participants at High Risk for Invasive Fungal Infections (MK-5592-120)

Study Overview
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Brief Summary
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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.

Official Title
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Pharmacokinetics and Safety of Intravenous Posaconazole (MK-5592, POS) in Chinese Subjects at High Risk for Invasive Fungal Infections

Conditions
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Fungal Infection

Intervention / Treatment
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* Drug: Posaconazole


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Posaconazole<br>All participants will receive posaconazole 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 will received posaconazole 300 mg IV infusion once daily or 200 mg oral suspension three times daily for up to 18 additional days. | Drug: Posaconazole<br>* Posaconazole 18 mg/mL IV solution; posaconazole 40 mg/mL oral suspension<br>* Other names: Noxafil;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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 | 
| 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. | 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 | 
| 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. | 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 | 
| 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. | 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 | 
| 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. | 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 | 
| 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. | 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 | 
| 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. | 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 | 
| 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 | Day 3, Day 6, Day 10, Day 15, Day 22, Day 28 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Up to 58 days | 
| 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. | Up to 28 days | 
| Medically Significant Changes in Clinical Laboratory Results - Lab Values | The number of participants with clinical laboratory values outside of normal range | Up to 28 days | 
| Medically Significant Changes in Clinical Laboratory Results - Vital Signs | The number of participants with values of vital signs outside of normal range | Up to 28 days | 
| 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 | Up to 98 days | 
| Participants With Invasive Fungal Infection (IFI) | Number of participants with possible, probable, or proven IFI observed during the whole study period | Up to 28 days |