Pharmacokinetics and Safety of Oral Posaconazole (MK-5592)Tablets in Chinese Participants at High Risk for Invasive Fungal Infections (MK-5592-117)

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

Status

Completed

Phases

Phase 1

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT02387983

Enrollment

Registered

2015-03-13

Start date

2015-05-06

Completion date

2016-05-02

Last updated

2018-10-09

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Fungal Infection

Brief summary

The purpose of this study is to evaluate the pharmacokinetics and safety of oral posaconazole tablets 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.

Interventions

DRUGPosaconazole

Posaconazole 300 mg solid oral tablet

Study design

Allocation

Intervention model

SINGLE_GROUP

Primary purpose

PREVENTION

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

18 Years to 70 Years

Healthy volunteers

Inclusion criteria

* Chinese participant * Female of reproductive potential with a serum hCG level consistent with a nongravid state and agree to use 2 acceptable methods of birth control throughout the study * Body Mass Index (BMI) \>=15 and \<=30 kg/m\^2 * 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) or 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

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
Steady-state Average Concentration (ssCavg) of Posaconazole on Day 8	Pre-dose and 2, 4, 6, 8, 12, and 24 hours post-dose on Day 8	The ssCavg was calculated in order to determine the percentage of participants achieving the pharmacokinetic (PK) target of ssCavg \>500 ng/mL on Day 8 when plasma drug levels had reached steady state.
Steady-state Area Under the Concentration-time Curve (ssAUC0-24hr) of Posaconazole on Day 8	Pre-dose and 2, 4, 6, 8, 12, and 24 hours post-dose on Day 8	The ssAUC0-24hr was calculated to determine the mean plasma drug concentration in the Intensive and Sparse PK subgroup from immediately after dosing to 24 hours post-dose on Day 8. Results data are presented as the arithmetic mean (% arithmetic coefficient of variation \[CV\]), where CV is calculated as (100 x standard deviation/arithmetic mean).
Steady-state Maximum Concentration (ssCmax) of Posaconazole on Day 8	Pre-dose and 2, 4, 6, 8, 12, and 24 hours post-dose on Day 8	The ssCmax was calculated in order to determine the maximum post-dose plasma drug concentration in the Intensive and Sparse PK subgroup on Day 8. Results data are presented as the arithmetic mean (% arithmetic coefficient of variation \[CV\]), where CV is calculated as (100 x standard deviation/arithmetic mean).
Steady-state Minimum Concentration (ssCmin) of Posaconazole on Day 8	Pre-dose and 2, 4, 6, 8, 12, and 24 hours post-dose on Day 8	The ssCmin was calculated in order to determine the lowest measurable drug concentration in the Intensive and Sparse PK subgroup up to 24 hours post-dose on Day 8. Results data are presented as the arithmetic mean (% arithmetic coefficient of variation \[CV\]), where CV is calculated as (100 x standard deviation/arithmetic mean).
Time to Steady-state Maximum Concentration (ssTmax) of Posaconazole on Day 8	Pre-dose and 2, 4, 6, 8, 12, and 24 hours post-dose on Day 8	The ssTmax was calculated in order to determine the amount of time required to reach ssCmax in the Intensive and Sparse PK subgroup on Day 8.
AUC0-24hr of Posaconazole on Day 1	Pre-dose and 2, 4, 6, 8, 12, and 24 hours post-dose on Day 1	The AUC0-24hr was calculated to determine the mean plasma drug concentration from immediately after dosing to 24 hours post-dose in the Immediate and Sparse PK subgroup on Day 1. Results data are presented as the arithmetic mean (% arithmetic coefficient of variation \[CV\]), where CV is calculated as (100 x standard deviation/arithmetic mean).
Cmax of Posaconazole on Day 1	Pre-dose and 2, 4, 6, 8, 12, and 24 hours post-dose on Day 1	The Cmax was calculated to determine the maximum plasma drug concentration up to 24 hours post-dose in the Immediate and Sparse PK subgroup on Day 1. Results data are presented as the arithmetic mean (% arithmetic coefficient of variation \[CV\]), where CV is calculated as (100 x standard deviation/arithmetic mean).
Cmin of Posaconazole on Day 1	Pre-dose and 2, 4, 6, 8, 12, and 24 hours post-dose on Day 1	The Cmin was calculated in order to determine the lowest measurable drug concentration from immediately after dosing to 24 hours post-dose in the Immediate and Sparse PK subgroup on Day 1. Results data are presented as the arithmetic mean (% arithmetic coefficient of variation \[CV\]), where CV is calculated as (100 x standard deviation/arithmetic mean).
Tmax of Posaconazole on Day 1	Pre-dose and 2, 4, 6, 8, 12, and 24 hours post-dose on Day 1	The Tmax was calculated in order to determine the time required to reach Cmax in the Immediate and Sparse PK subgroup on Day 1.

Participant flow

Recruitment details

Adult (18 to 70 years of age) male and female participants with neutropenia undergoing chemotherapy for acute myelogenous leukemia (AML) or myelodysplastic syndromes (MDS) were recruited at 4 sites in China.

Participants by arm

Arm	Count
Posaconazole All participants received posaconazole 300 mg tablet (3 x 100 mg tablets) once every 12 hours on Day 1 and once-daily on Days 2 to 28. The first 20 participants (Intensive and Sparse PK subgroup) underwent intensive and sparse pharmacokinetic (PK) sampling on Days 1 and 8; the next 45 participants (Sparse PK subgroup) underwent PK sampling on Day 8 only.	65
Total	65

Withdrawals & dropouts

Period	Reason	FG000
Overall Study	Adverse Event	4
Overall Study	Protocol Violation	1
Overall Study	Withdrawal by Subject	2

Baseline characteristics

Characteristic	Posaconazole
Age, Continuous	42.7 Years STANDARD_DEVIATION 11.8
Sex: Female, Male Female	30 Participants
Sex: Female, Male Male	35 Participants

Adverse events

Event type	EG000 affected / at risk
deaths Total, all-cause mortality	— / —
other Total, other adverse events	64 / 65
serious Total, serious adverse events	4 / 65

Outcome results

Primary

AUC0-24hr of Posaconazole on Day 1

The AUC0-24hr was calculated to determine the mean plasma drug concentration from immediately after dosing to 24 hours post-dose in the Immediate and Sparse PK subgroup on Day 1. Results data are presented as the arithmetic mean (% arithmetic coefficient of variation \[CV\]), where CV is calculated as (100 x standard deviation/arithmetic mean).

Time frame: Pre-dose and 2, 4, 6, 8, 12, and 24 hours post-dose on Day 1

Population: The PK analysis set included all randomized and treated participants in the Intensive and Sparse PK subgroup who complied with the protocol and have documented adherence to daily dosing and PK regimens through the Day 8 steady-state evaluation with available data.

Arm	Measure	Value (MEAN)	Dispersion
Posaconazole	AUC0-24hr of Posaconazole on Day 1	14500 hr*ng/mL	Standard Deviation 39

Primary

Cmax of Posaconazole on Day 1

The Cmax was calculated to determine the maximum plasma drug concentration up to 24 hours post-dose in the Immediate and Sparse PK subgroup on Day 1. Results data are presented as the arithmetic mean (% arithmetic coefficient of variation \[CV\]), where CV is calculated as (100 x standard deviation/arithmetic mean).

Time frame: Pre-dose and 2, 4, 6, 8, 12, and 24 hours post-dose on Day 1

Population: The PK analysis set included all randomized and treated participants in the Immediate and Sparse PK subgroup who complied with the protocol and have documented adherence to daily dosing and PK regimens through the Day 8 steady-state evaluation with available data.

Arm	Measure	Value (MEAN)	Dispersion
Posaconazole	Cmax of Posaconazole on Day 1	730 ng/mL	Standard Deviation 47.7

Primary

Cmin of Posaconazole on Day 1

The Cmin was calculated in order to determine the lowest measurable drug concentration from immediately after dosing to 24 hours post-dose in the Immediate and Sparse PK subgroup on Day 1. Results data are presented as the arithmetic mean (% arithmetic coefficient of variation \[CV\]), where CV is calculated as (100 x standard deviation/arithmetic mean).

Time frame: Pre-dose and 2, 4, 6, 8, 12, and 24 hours post-dose on Day 1

Arm	Measure	Value (MEAN)	Dispersion
Posaconazole	Cmin of Posaconazole on Day 1	997 ng/mL	Standard Deviation 35.9

Primary

Steady-state Area Under the Concentration-time Curve (ssAUC0-24hr) of Posaconazole on Day 8

The ssAUC0-24hr was calculated to determine the mean plasma drug concentration in the Intensive and Sparse PK subgroup from immediately after dosing to 24 hours post-dose on Day 8. Results data are presented as the arithmetic mean (% arithmetic coefficient of variation \[CV\]), where CV is calculated as (100 x standard deviation/arithmetic mean).