Assessment of Pharmacokinetics of Single Dose Odanacatib (MK-0822) in Participants With Moderate Hepatic Insufficiency (MK-0822-070)

• Sponsor: Merck Sharp & Dohme LLC (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01512693
• Collaborator: (none)
• Enrollment: 17
• Arms: 2
• Actual Duration (Months): 2

Study Details

Study Description

Brief Summary

This open-label, non-randomized study was designed to compare pharmacokinetics of a single 50 milligram (mg) dose of MK-0822 in participants with and without moderate hepatic insufficiency (abnormal liver function) in order to determine to what degree hepatic dysfunction may impact therapeutic blood levels of MK-0822. The primary hypothesis is that plasma AUC0-∞ of odanacatib in participants with moderate hepatic insufficiency is similar to that in matched healthy participants following a single 50 mg oral dose.

Condition or Disease	Intervention/Treatment	Phase
Hepatic Insufficiency	Drug: MK-0822	Phase 1

Study Design

• Study Type: Interventional
• Actual Enrollment: 17 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Single Dose Study to Investigate the Pharmacokinetics of Odanacatib (MK-0822) in Subjects With Hepatic Insufficiency
• Actual Study Start Date: Feb 23, 2012
• Actual Primary Completion Date: Apr 24, 2012
• Actual Study Completion Date: Apr 24, 2012

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Moderate Hepatic Insufficiency Group Single-dose administration of odanacatib 50 mg to participants with moderate hepatic insufficiency.	Drug: MK-0822; A single oral dose (50 mg tablet) of MK 0822 will be administered on Day 1 after an overnight fast.; Other Names: odanacatib
Experimental: Healthy Matched Control Group Single-dose administration of odanacatib 50 mg to healthy matched control participants.	Drug: MK-0822; A single oral dose (50 mg tablet) of MK 0822 will be administered on Day 1 after an overnight fast.; Other Names: odanacatib

Outcome Measures

Primary Outcome Measures

1. Area Under the Concentration-time Curve of MK-0822 From Time 0 to Infinity (AUC0-∞) After Single Dose [Pre-dose and 1, 2, 4, 6, 9, 12, 16, 24, 32, 48, 72, 96, 120, 168, 240, and 336 hours postdose]

   For healthy and moderate hepatic insufficiency participants, plasma samples were collected from predose to 336 hours postdose for determination of AUC0-∞ (Total AUC). AUC0-∞ is a measure of total drug exposure.

Secondary Outcome Measures

1. Maximum Concentration (Cmax) of MK-0822 After Single Dose [Pre-dose and 1, 2, 4, 6, 9, 12, 16, 24, 32, 48, 72, 96, 120, 168, 240, and 336 hours postdose]

   For healthy and moderate hepatic insufficiency participants, plasma samples were collected from predose to 336 hours postdose for determination of Cmax.

2. Time to Maximum Concentration (Tmax) of MK-0822 After Single Dose [Pre-dose and 1, 2, 4, 6, 9, 12, 16, 24, 32, 48, 72, 96, 120, 168, 240, and 336 hours postdose]

   For healthy and moderate hepatic insufficiency participants, plasma samples were collected from predose to 336 hours postdose for determination of Tmax.

3. Apparent Terminal Half-life (t1/2) of MK-0822 After Single Dose [Pre-dose and 1, 2, 4, 6, 9, 12, 16, 24, 32, 48, 72, 96, 120, 168, 240, and 336 hours postdose]

   Apparent terminal half-life is the time required to divide the plasma (serum) concentration by two after reaching pseudo-equilibrium. (Note: it is not the time required to eliminate half the administered dose.) For healthy and moderate hepatic insufficiency participants, plasma samples were collected from predose to 336 hours postdose for determination of t1/2. Results are presented using harmonic mean and jackknife standard deviation.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 70 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

• Not currently pregnant, nursing or planning to be pregnant through-out the course of the study; agree to use specified contraception per protocol requirement

• Body Mass Index (BMI) of ≤ 39 kg/m^2 (not obese)

• Judged to be in good health (for healthy participant population)

• Non-smoker for the past 6-months; social smokers (smoke less than 10 cigarettes within the past 3 months; or per discretion of the study Investigator, quit smoking within the past 3 months.

• Diagnosed with chronic (more than 6 months), stable (no acute episodes of illness within the previous 2 months) hepatic insufficiency (liver dysfunction) with features of cirrhosis due to any cause (for the moderate hepatic insufficiency participant population)

• Possess the ability to understand the study, grant voluntary informed consent and willingly comply with all study requirements

Exclusion Criteria:

• Does not meet the age requirement, is mentally or legally incapacitated, has or is expected to have significant emotional problems, or a history of a clinically significant psychiatric disorder

• Has been diagnosed with a disease or medical condition which may pose a risk to the participant or may confound the study results

• Compromised renal (kidney) function, significant organ system disease(s) or cancer(s)

• Unable to refrain from or anticipates the use of any new medication, including prescription and non-prescription drugs or herbal remedies

• Meets the requirements of the study in regard to current medication profile including: prescribed medications, caffeine, alcohol, over-the-counter drugs, herbals and nutritional products; with expected non-use of recreational (illicit) drugs associated with misuse, abuse and/or addiction

• Had surgery, donated 1 unit of blood or received another investigational study medication within 4 weeks prior to the study's first dose of investigational product

• History of multiple and/or severe allergies, or has had a life-threatening reaction or inability to tolerate prescription or non-prescription drugs or food

Contacts and Locations

Locations

No locations specified.

Sponsors and Collaborators

• Merck Sharp & Dohme LLC

Investigators

• Study Director: Medical Director, Merck Sharp & Dohme LLC

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Merck Sharp & Dohme LLC
• ClinicalTrials.gov Identifier: NCT01512693
• Other Study ID Numbers: 0822-070
• First Posted: Jan 19, 2012
• Last Update Posted: Aug 29, 2018
• Last Verified: Jul 1, 2018

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Hepatic Insufficiency; Liver Failure

Study Results

Participant Flow

Arm/Group Title	Moderate Hepatic Insufficiency Group	Healthy Matched Control Group
Arm/Group Description	Single-dose administration of odanacatib 50 mg to participants with moderate hepatic insufficiency.	Single-dose administration of odanacatib 50 mg to healthy matched control participants.
Period Title: Overall Study
STARTED	8	9
COMPLETED	8	8
NOT COMPLETED	0	1

Baseline Characteristics

Arm/Group Title	Moderate Hepatic Insufficiency Group	Healthy Matched Control Group	Total
Arm/Group Description	Single-dose administration of odanacatib 50 mg to participants with moderate hepatic insufficiency.	Single-dose administration of odanacatib 50 mg to healthy matched control participants.	Total of all reporting groups
Overall Participants	8	9	17
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	53.1 (4.9)	54.2 (5.3)	53.7 (5.0)
Sex: Female, Male (Count of Participants)
Female	1 12.5%	1 11.1%	2 11.8%
Male	7 87.5%	8 88.9%	15 88.2%

Outcome Measures

1. Primary Outcome

Title	Area Under the Concentration-time Curve of MK-0822 From Time 0 to Infinity (AUC0-∞) After Single Dose
Description	For healthy and moderate hepatic insufficiency participants, plasma samples were collected from predose to 336 hours postdose for determination of AUC0-∞ (Total AUC). AUC0-∞ is a measure of total drug exposure.
Time Frame	Pre-dose and 1, 2, 4, 6, 9, 12, 16, 24, 32, 48, 72, 96, 120, 168, 240, and 336 hours postdose

Outcome Measure Data

Analysis Population Description

The per protocol population consisted of all participants who complied with the protocol sufficiently to ensure that results will likely exhibit the effects of treatment according to the underlying scientific model.

Arm/Group Title	Moderate Hepatic Insufficiency Group	Healthy Matched Control Group
Arm/Group Description	Single-dose administration of odanacatib 50 mg to participants with moderate hepatic insufficiency.	Single-dose administration of odanacatib 50 mg to healthy matched control participants.
Measure Participants	8	8
Least Squares Mean (95% Confidence Interval) [μM*hr]	28.84	33.79

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Moderate Hepatic Insufficiency Group, Healthy Matched Control Group
	Comments	Natural log-transformed plasma values were analyzed using an analysis of covariance (ANCOVA) model with a categorical factor for population (moderate hepatic insufficiency participants, healthy matched control participants) and continuous covariates for age and body mass index (BMI). Data are back transformed to geometric least-squares mean ratio (GMR) (moderate hepatic insufficiency / healthy) and 90% confidence intervals.
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Similarity will be concluded if the GMR (moderate hepatic insufficiency / healthy) is contained within the interval [0.40, 2.50].
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	GMR
	Estimated Value	0.85
	Confidence Interval	(2-Sided) 90%; 0.61 to 1.19
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Maximum Concentration (Cmax) of MK-0822 After Single Dose
Description	For healthy and moderate hepatic insufficiency participants, plasma samples were collected from predose to 336 hours postdose for determination of Cmax.
Time Frame	Pre-dose and 1, 2, 4, 6, 9, 12, 16, 24, 32, 48, 72, 96, 120, 168, 240, and 336 hours postdose

Outcome Measure Data

Analysis Population Description

The per protocol population consisted of all participants who complied with the protocol sufficiently to ensure that results will likely exhibit the effects of treatment according to the underlying scientific model.

Arm/Group Title	Moderate Hepatic Insufficiency Group	Healthy Matched Control Group
Arm/Group Description	Single-dose administration of odanacatib 50 mg to participants with moderate hepatic insufficiency.	Single-dose administration of odanacatib 50 mg to healthy matched control participants.
Measure Participants	8	8
Least Squares Mean (95% Confidence Interval) [nM]	199.41	279.59

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Moderate Hepatic Insufficiency Group, Healthy Matched Control Group
	Comments	Natural log-transformed plasma values were analyzed using an ANCOVA model with a categorical factor for population (moderate hepatic insufficiency participants, healthy matched control participants) and continuous covariates for age and BMI. Data are back transformed to GMR (moderate hepatic insufficiency / healthy) and 90% confidence intervals.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	GMR
	Estimated Value	0.71
	Confidence Interval	(2-Sided) 90%; 0.51 to 1.00
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Time to Maximum Concentration (Tmax) of MK-0822 After Single Dose
Description	For healthy and moderate hepatic insufficiency participants, plasma samples were collected from predose to 336 hours postdose for determination of Tmax.
Time Frame	Pre-dose and 1, 2, 4, 6, 9, 12, 16, 24, 32, 48, 72, 96, 120, 168, 240, and 336 hours postdose

Outcome Measure Data

Analysis Population Description

The per protocol population consisted of all participants who complied with the protocol sufficiently to ensure that results will likely exhibit the effects of treatment according to the underlying scientific model.

Arm/Group Title	Moderate Hepatic Insufficiency Group	Healthy Matched Control Group
Arm/Group Description	Single-dose administration of odanacatib 50 mg to participants with moderate hepatic insufficiency.	Single-dose administration of odanacatib 50 mg to healthy matched control participants.
Measure Participants	8	8
Median (Full Range) [hr]	4.00	24.00

4. Secondary Outcome

Title	Apparent Terminal Half-life (t1/2) of MK-0822 After Single Dose
Description	Apparent terminal half-life is the time required to divide the plasma (serum) concentration by two after reaching pseudo-equilibrium. (Note: it is not the time required to eliminate half the administered dose.) For healthy and moderate hepatic insufficiency participants, plasma samples were collected from predose to 336 hours postdose for determination of t1/2. Results are presented using harmonic mean and jackknife standard deviation.
Time Frame	Pre-dose and 1, 2, 4, 6, 9, 12, 16, 24, 32, 48, 72, 96, 120, 168, 240, and 336 hours postdose

Outcome Measure Data

Analysis Population Description

The per protocol population consisted of all participants who complied with the protocol sufficiently to ensure that results will likely exhibit the effects of treatment according to the underlying scientific model.

Arm/Group Title	Moderate Hepatic Insufficiency Group	Healthy Matched Control Group
Arm/Group Description	Single-dose administration of odanacatib 50 mg to participants with moderate hepatic insufficiency.	Single-dose administration of odanacatib 50 mg to healthy matched control participants.
Measure Participants	8	8
Mean (Standard Deviation) [hr]	91.5 (30.1)	70.5 (10.2)

Adverse Events

Time Frame	Up to 15 days
Adverse Event Reporting Description	The safety population consisted of all participants who received at least one dose of the study drug.
Arm/Group Title	Moderate Hepatic Insufficiency Group		Healthy Matched Control Group
Arm/Group Description	Single-dose administration of odanacatib 50 mg to participants with moderate hepatic insufficiency.		Single-dose administration of odanacatib 50 mg to healthy matched control participants.
All Cause Mortality
	Moderate Hepatic Insufficiency Group		Healthy Matched Control Group
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Moderate Hepatic Insufficiency Group		Healthy Matched Control Group
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/8 (0%)		0/9 (0%)
Other (Not Including Serious) Adverse Events
	Moderate Hepatic Insufficiency Group		Healthy Matched Control Group
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/8 (12.5%)		1/9 (11.1%)
Infections and infestations
Nasopharynigitis	1/8 (12.5%)	1	0/9 (0%)	0
Nervous system disorders
Headache	0/8 (0%)	0	1/9 (11.1%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.