Pharmacokinetics of Sugammadex (MK-8616) in Participants With Moderate and Severe Renal Insufficiency (MK-8616-105)

An Open-Label, Single-Dose Study to Investigate the Pharmacokinetics of MK-8616 in Subjects With Moderate and Severe Renal Insufficiency

The purpose of this study is to evaluate the plasma pharmacokinetics of a single 4 mg/kg intravenous (IV) dose of sugammadex in participants with moderate and severe renal insufficiency compared to that in participants with normal renal function. The study consists of two parts. In Part 1, participants with renal insufficiency and healthy participants will be administered study drug by IV bolus injection into a peripheral vein. In Part 2, participants with renal insufficiency and healthy participants will be administered study drug as an IV bolus into a peripheral vein, through an IV catheter connected to IV tubing with injection port. Subjects who participate in Part 1 of study may be enrolled in Part 2, which would reduce the overall number of participants enrolled for the study.

Study Overview

• Status: Completed
• Conditions: Renal Insufficiency; Renal Impairment
• Intervention / Treatment: Drug: sugammadex

Detailed Description

In each study period (i.e., Part 1 and Part 2), day of drug administration was defined to be Day 1.

• Study Type: Interventional
• Enrollment (Actual): 33
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Florida
    • Hialeah, Florida, United States, 33014
      • Investigational Site 001

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

All Participants:

• Body Mass Index ≥18 to ≤40 kg/m^2
• Females of childbearing potential must either be sexually inactive (abstinent) for 14 days prior to dosing and throughout the study or are using an acceptable birth control method
• Females of non-childbearing potential must have undergone a sterilization procedure at least 6 months prior to dosing or are postmenopausal with amenorrhea for at least 1 year prior to dosing and have follicle stimulating hormone (FSH) serum levels consistent with postmenopausal status
• Male subjects must agree not to donate sperm from dosing until 90 days after dosing

Participants with Moderate or Severe Renal Insufficiency:

• Health of participant is stable based on medical history, laboratory tests and other assessments
• Clinical diagnosis of impaired stable renal function, and a creatinine clearance (CLcr) of <30 mL/min and not on hemodialysis for severe renal insufficiency participants, or 30 to <50 mL/min for moderate renal insufficiency participants
• No clinically significant change in renal status for at least 1 month prior to dosing, and is not currently or has not previously been on hemodialysis

Healthy Control Participants:

• Participant is medically healthy based on laboratory tests and other assessments
• Age of the individual healthy participants in Part 1 of the study is aimed to be within the range of the mean age ± approximately 15 years of all participants with renal impairment in Part 1 of the study combined; this approach will also be applied with respect to age of participants in Part 2 of the study
• CLcr ≥80 mL/min

Exclusion Criteria:

All Participants:

• Mentally or legally incapacitated, significant emotional problems at screening or expected during the conduct of the study or history of a clinically significant psychiatric disorder over the last 5 years
• History or presence of significant cardiovascular, pulmonary, hepatic, renal, hematological, gastrointestinal, endocrine, immunologic, dermatologic, or neurological disease whose current condition is considered unstable
• History or presence of alcoholism and drug abuse within the past 6 months
• History or presence of hypersensitivity or idiosyncratic reaction to the study medication or related compounds
• Female participants who are pregnant or lactating
• Positive results for the urine or saliva drug screen, or for the urine or breath alcohol screen
• Positive results at screening for human immunodeficiency virus (HIV), hepatitis B surface antigen (HBsAg) or hepatitis C virus (HCV)
• Regular user of any medication (including over the counter) that would significantly alter renal function (e.g., cimetidine)
• Donation of blood or significant blood loss within 56 days prior to dosing, or donation of plasma within 7 days prior to dosing
• Participation in another clinical trial within 28 days prior to dosing
• No participant may be enrolled more than once within Part 1. Subjects who participate in Part 1 of study may be enrolled in Part 2, but participants within Part 2 are not to be enrolled more than once in Part 2

Healthy Control Participants:

• Participant has had a renal transplant or has had nephrectomy

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Severe Renal Insufficiency Participants: Part 1; Participants with severe renal insufficiency will receive a single dose of 4 mg/kg sugammadex administered as an IV bolus over 10 seconds. Dose will be administered by direct injection into a peripheral vein.	Drug: sugammadex; sugammadex 4 mg/kg IV bolus
Experimental: Moderate Renal Insufficiency Participants: Part 1; Participants with moderate renal insufficiency will receive a single dose of 4 mg/kg sugammadex administered as an IV bolus over 10 seconds. Dose will be administered by direct injection into a peripheral vein.	Drug: sugammadex; sugammadex 4 mg/kg IV bolus
Experimental: Healthy Control Participants: Part 1; Healthy control participants will receive a single dose of 4 mg/kg sugammadex administered as an IV bolus over 10 seconds. Dose will be administered by direct injection into a peripheral vein.	Drug: sugammadex; sugammadex 4 mg/kg IV bolus
Experimental: Severe Renal Insufficiency Participants: Part 2; Participants with severe renal insufficiency will receive a single dose of 4 mg/kg sugammadex administered as an IV bolus over 10 seconds. Dose will be administered into a peripheral vein through an IV catheter connected to an IV tubing with injection port. The IV tubing is connected to a saline bag. Free-flowing access to the vein will be confirmed immediately prior to dose administration, and dose will be followed by saline flush.	Drug: sugammadex; sugammadex 4 mg/kg IV bolus
Experimental: Moderate Renal Insufficiency Participants: Part 2; Participants with moderate renal insufficiency will receive a single dose of 4 mg/kg sugammadex administered as an IV bolus over 10 seconds. Dose will be administered into a peripheral vein through an IV catheter connected to an IV tubing with injection port. The IV tubing is connected to a saline bag. Free-flowing access to the vein will be confirmed immediately prior to dose administration, and dose will be followed by saline flush.	Drug: sugammadex; sugammadex 4 mg/kg IV bolus
Experimental: Healthy Control Participants: Part 2; Healthy control participants will receive a single dose of 4 mg/kg sugammadex administered as an IV bolus over 10 seconds. Dose will be administered into a peripheral vein through an IV catheter connected to an IV tubing with injection port. The IV tubing is connected to a saline bag. Free-flowing access to the vein will be confirmed immediately prior to dose administration, and dose will be followed by saline flush.	Drug: sugammadex; sugammadex 4 mg/kg IV bolus

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Geometric Least Squares Mean Area Under the Plasma Drug Concentration-time Curve From Time Zero to Infinity (AUC0-∞) Following a Single IV Dose of Sugammadex	Plasma samples for determination of sugammadex pharmacokinetic parameters were obtained pre-dose and at specified post-dose time points. AUC0-∞ was calculated as the sum of the AUC to the last time point with a detectable plasma concentration (AUC0-last, determined by trapezoidal method) and the extrapolated area given by Cest,last/λz, where Cest,last is the estimated concentration corresponding to the time of the last measurable concentration and λz is the apparent first-order terminal elimination rate constant. For each subject, λz was calculated by regression of the terminal log-linear portion of the plasma concentration-time profile. The reported least squares mean is the geometric least squares mean, which is the back-transformed least squares mean from the analysis of variance (ANOVA) linear fixed-effect model performed on natural log-transformed values of AUC0-∞. This calculation also provides the associated 95% confidence interval.	For participants with: normal renal function - up to 48 hours post-dose (Part 1 + Part 2); moderate renal insufficiency - up to Day 28 (Part 1) or Day 10 (Part 2); severe renal insufficiency - up to Day 35 (Part 1) or Day 14 (Part 2)
Geometric Least Squares Mean Area Under the Plasma Concentration Versus Time Curve From Time Zero to the Last Measurable Concentration (AUC0-last) Following a Single IV Dose of Sugammadex	Plasma samples for determination of sugammadex pharmacokinetic parameters were obtained pre-dose and at specified post-dose time points. AUC0-last was determined by trapezoidal method. The reported least squares mean is the geometric least squares mean, which is the back-transformed least squares mean from the ANOVA linear fixed-effect model performed on natural log-transformed values of AUC0-last. This calculation also provides the associated 95% confidence interval.	For participants with: normal renal function - up to 48 hours post-dose (Part 1 + Part 2); moderate renal insufficiency - up to Day 28 (Part 1) or Day 10 (Part 2); severe renal insufficiency - up to Day 35 (Part 1) or Day 14 (Part 2)
Geometric Least Squares Mean Maximum Observed Plasma Concentration (Cmax) Following a Single IV Dose of Sugammadex	Plasma samples for determination of sugammadex pharmacokinetic parameters were obtained pre-dose and at specified post-dose time points. Cmax was determined from the observed plasma concentration-time data. The reported least squares mean is the geometric least squares mean, which is the back-transformed least squares mean from the ANOVA linear fixed-effect model performed on natural log-transformed values of Cmax. This calculation also provides the associated 95% confidence interval.	For participants with: normal renal function - up to 48 hours post-dose (Part 1 + Part 2); moderate renal insufficiency - up to Day 28 (Part 1) or Day 10 (Part 2); severe renal insufficiency - up to Day 35 (Part 1) or Day 14 (Part 2)
Geometric Mean Percent of AUC0-∞ That Was Extrapolated (AUC%Extrap) Following a Single IV Dose of Sugammadex	Plasma samples for determination of sugammadex pharmacokinetic parameters were obtained pre-dose and at specified post-dose time points. AUC%extrap represents the percentage of the AUC0-∞ obtained by extrapolation, calculated as (1 - [AUC0-last/AUC0-∞]) multiplied by 100.	For participants with: normal renal function - up to 48 hours post-dose (Part 1 + Part 2); moderate renal insufficiency - up to Day 28 (Part 1) or Day 10 (Part 2); severe renal insufficiency - up to Day 35 (Part 1) or Day 14 (Part 2)
Geometric Mean Total Clearance (CL) Following a Single IV Dose of Sugammadex	Plasma samples for determination of sugammadex pharmacokinetic parameters were obtained pre-dose and at specified post-dose time points. CL is a quantitative measure of the rate at which a drug substance is removed from the body, calculated as Dose/AUC0-∞.	For participants with: normal renal function - up to 48 hours post-dose (Part 1 + Part 2); moderate renal insufficiency - up to Day 28 (Part 1) or Day 10 (Part 2); severe renal insufficiency - up to Day 35 (Part 1) or Day 14 (Part 2)
Geometric Mean Volume of Distribution During the Terminal Elimination Phase (Vz) Following a Single IV Dose of Sugammadex	Plasma samples for determination of sugammadex pharmacokinetic parameters were obtained pre-dose and at specified post-dose time points. Vz was calculated as Dose/(AUC0-∞*λz).	For participants with: normal renal function - up to 48 hours post-dose (Part 1 + Part 2); moderate renal insufficiency - up to Day 28 (Part 1) or Day 10 (Part 2); severe renal insufficiency - up to Day 35 (Part 1) or Day 14 (Part 2)
Geometric Mean of Mean Residence Time (MRT) of Unchanged Drug in the Systemic Circulation Following a Single IV Dose of Sugammadex	Plasma samples for determination of sugammadex pharmacokinetic parameters were obtained pre-dose and at specified post-dose time points. MRT is defined as the mean duration of time a drug molecule is present in the systemic circulation.	For participants with: normal renal function - up to 48 hours post-dose (Part 1 + Part 2); moderate renal insufficiency - up to Day 28 (Part 1) or Day 10 (Part 2); severe renal insufficiency - up to Day 35 (Part 1) or Day 14 (Part 2)
Geometric Mean Apparent Volume of Distribution Estimated at Steady-state (Vss) Following a Single IV Dose of Sugammadex	Plasma samples for determination of sugammadex pharmacokinetic parameters were obtained pre-dose and at specified post-dose time points. Vss is the theoretical volume that the total amount of administered drug would have to occupy (if it were uniformly distributed), to provide the same concentration as it is in blood plasma at steady state, calculated as CL*MRT.	For participants with: normal renal function - up to 48 hours post-dose (Part 1 + Part 2); moderate renal insufficiency - up to Day 28 (Part 1) or Day 10 (Part 2); severe renal insufficiency - up to Day 35 (Part 1) or Day 14 (Part 2)
Median Time to Maximum Observed Plasma Concentration (Tmax) Following a Single IV Dose of Sugammadex	Plasma samples for determination of sugammadex pharmacokinetic parameters were obtained pre-dose and at specified post-dose time points. Tmax was determined from the observed plasma concentration-time data.	For participants with: normal renal function - up to 48 hours post-dose (Part 1 + Part 2); moderate renal insufficiency - up to Day 28 (Part 1) or Day 10 (Part 2); severe renal insufficiency - up to Day 35 (Part 1) or Day 14 (Part 2)
Median Time of the Last Measurable Plasma Concentration (Tlast) Following a Single IV Dose of Sugammadex	Plasma samples for determination of sugammadex pharmacokinetic parameters were obtained pre-dose and at specified post-dose time points. Tlast was determined from the observed plasma concentration-time data.	For participants with: normal renal function - up to 48 hours post-dose (Part 1 + Part 2); moderate renal insufficiency - up to Day 28 (Part 1) or Day 10 (Part 2); severe renal insufficiency - up to Day 35 (Part 1) or Day 14 (Part 2)
Geometric Mean Apparent First-order Terminal Elimination Half-life (t1/2) Following a Single IV Dose of Sugammadex	Plasma samples for determination of sugammadex pharmacokinetic parameters were obtained pre-dose and at specified post-dose time points. Elimination t1/2 is the time it takes for the concentration of the drug in the body to decrease by half during the elimination phase, calculated as the natural log of 2 (ln[2])/λz.	For participants with: normal renal function - up to 48 hours post-dose (Part 1 + Part 2); moderate renal insufficiency - up to Day 28 (Part 1) or Day 10 (Part 2); severe renal insufficiency - up to Day 35 (Part 1) or Day 14 (Part 2)
Geometric Mean Effective Half-life (t1/2eff) Following a Single IV Dose of Sugammadex	Plasma samples for determination of sugammadex pharmacokinetic parameters were obtained pre-dose and at specified post-dose time points. t½eff was calculated as ln(2)*MRT.	For participants with: normal renal function - up to 48 hours post-dose (Part 1 + Part 2); moderate renal insufficiency - up to Day 28 (Part 1) or Day 10 (Part 2); severe renal insufficiency - up to Day 35 (Part 1) or Day 14 (Part 2)
Geometric Mean Apparent First-order Terminal Elimination Rate Constant (λz) Following a Single IV Dose of Sugammadex	Plasma samples for determination of sugammadex pharmacokinetic parameters were obtained pre-dose and at specified post-dose time points. λz was calculated by regression of the terminal log-linear portion of the plasma concentration-time profile.	For participants with: normal renal function - up to 48 hours post-dose (Part 1 + Part 2); moderate renal insufficiency - up to Day 28 (Part 1) or Day 10 (Part 2); severe renal insufficiency - up to Day 35 (Part 1) or Day 14 (Part 2)

Collaborators and Investigators

• Sponsor: Merck Sharp & Dohme LLC

Publications and helpful links

General Publications

• Min KC, Lasseter KC, Marbury TC, Wrishko RE, Hanley WD, Wolford DG, Udo de Haes J, Reitmann C, Gutstein DE. Pharmacokinetics of sugammadex in subjects with moderate and severe renal impairment . Int J Clin Pharmacol Ther. 2017 Sep;55(9):746-752. doi: 10.5414/CP203025.

Study record dates

Study Major Dates

• Study Start (Actual): December 11, 2013
• Primary Completion (Actual): June 6, 2014
• Study Completion (Actual): June 6, 2014

Study Registration Dates

• First Submitted: December 10, 2013
• First Submitted That Met QC Criteria: December 10, 2013
• First Posted (Estimate): December 13, 2013

Study Record Updates

• Last Update Posted (Actual): October 2, 2018
• Last Update Submitted That Met QC Criteria: September 4, 2018
• Last Verified: September 1, 2018

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Kidney Diseases; Urologic Diseases; Renal Insufficiency
• Other Study ID Numbers: 8616-105

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: https://www.merck.com/clinical-trials/pdf/ProcedureAccessClinicalTrialData.pdf

Study Data/Documents

1. CSR Synopsis