Renal Impairment, Renal Insufficiency
Conditions
Brief summary
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.
Detailed description
In each study period (i.e., Part 1 and Part 2), day of drug administration was defined to be Day 1.
Interventions
DRUGsugammadex
sugammadex 4 mg/kg IV bolus
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
Yes
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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 | 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) | 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. |
| 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 | 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) | 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. |
| Geometric Least Squares Mean Maximum Observed Plasma Concentration (Cmax) Following a Single IV Dose of Sugammadex | 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) | 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. |
| Geometric Mean Percent of AUC0-∞ That Was Extrapolated (AUC%Extrap) Following a Single IV Dose of Sugammadex | 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) | 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. |
| Geometric Mean Total Clearance (CL) Following a Single IV Dose of Sugammadex | 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) | 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-∞. |
| Geometric Mean Volume of Distribution During the Terminal Elimination Phase (Vz) Following a Single IV Dose of Sugammadex | 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) | 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). |
| Geometric Mean of Mean Residence Time (MRT) of Unchanged Drug in the Systemic Circulation Following a Single IV Dose of Sugammadex | 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) | 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. |
| Geometric Mean Apparent Volume of Distribution Estimated at Steady-state (Vss) Following a Single IV Dose of Sugammadex | 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) | 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. |
| Median Time to Maximum Observed Plasma Concentration (Tmax) Following a Single IV Dose of Sugammadex | 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) | 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. |
| Median Time of the Last Measurable Plasma Concentration (Tlast) Following a Single IV Dose of Sugammadex | 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) | 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. |
| Geometric Mean Apparent First-order Terminal Elimination Half-life (t1/2) Following a Single IV Dose of Sugammadex | 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) | 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. |
| Geometric Mean Effective Half-life (t1/2eff) Following a Single IV Dose of Sugammadex | 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) | 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. |
| Geometric Mean Apparent First-order Terminal Elimination Rate Constant (λz) Following a Single IV Dose of Sugammadex | 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) | 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. |
Countries
United States
Participant flow
Pre-assignment details
33 subjects participated in study. 9 participated in both Part 1 and Part 2; for these, separate Part 2 baseline assessments were obtained. Due to differing Part 1 and Part 2 baseline renal function result, 1 participant was in severe renal insufficiency group in Part 1 and moderate renal insufficiency group in Part 2.
Participants by arm
| Arm | Count |
|---|---|
| Severe Renal Insufficiency Participants: Part 1 + Part 2 This group includes participants with severe renal insufficiency who were included in Part 1, Part 2, or in both Part 1 and Part 2. Participants receive a single dose of 4 mg/kg sugammadex administered as an IV bolus over 10 seconds. In Part 1, dose is administered by direct injection into a peripheral vein. In Part 2, dose is administered into a peripheral vein through an IV catheter connected to an IV tubing with injection port. | 10 |
| Moderate Renal Insufficiency Participants: Part 1 + Part 2 This group includes participants with moderate renal insufficiency who were included in Part 1, Part 2, or in both Part 1 and Part 2. Participants receive a single dose of 4 mg/kg sugammadex administered as an IV bolus over 10 seconds. In Part 1, dose is administered by direct injection into a peripheral vein. In Part 2, dose is administered into a peripheral vein through an IV catheter connected to an IV tubing with injection port. | 11 |
| Healthy Control Participants: Part 1 + Part 2 This group includes healthy control participants who were included in Part 1, Part 2, or in both Part 1 and Part 2. Participants receive a single dose of 4 mg/kg sugammadex administered as an IV bolus over 10 seconds. In Part 1, dose is administered by direct injection into a peripheral vein. In Part 2, dose is administered into a peripheral vein through an IV catheter connected to an IV tubing with injection port. | 12 |
| Total | 33 |
Baseline characteristics
| Characteristic | Severe Renal Insufficiency Participants: Part 1 + Part 2 | Moderate Renal Insufficiency Participants: Part 1 + Part 2 | Healthy Control Participants: Part 1 + Part 2 | Total |
|---|---|---|---|---|
| Age, Continuous | 62.3 Years | 64.2 Years | 58.3 Years | 61.5 Years |
| Sex: Female, Male Female | 2 Participants | 1 Participants | 5 Participants | 8 Participants |
| Sex: Female, Male Male | 8 Participants | 10 Participants | 7 Participants | 25 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 3 / 8 | 2 / 8 | 2 / 8 | 1 / 6 | 2 / 6 | 0 / 6 |
| serious Total, serious adverse events | 0 / 8 | 0 / 8 | 0 / 8 | 0 / 6 | 0 / 6 | 0 / 6 |
Outcome results
Primary
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.
Time frame: 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)
Population: Pharmacokinetic analysis was performed only for Part 2 data for participants in Part 2. Analysis was not conducted for Part 1, as review of drug concentration data, and dosing issues noted at investigative sites, indicated that in some participants, doses may not have been administered directly into vein, and likely infiltrated surrounding tissue.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Severe Renal Insufficiency Participants: 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 | 335 ug*hr/mL |
| Moderate Renal Insufficiency Participants: 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 | 148 ug*hr/mL |
| Healthy Control Participants: 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 | 61.1 ug*hr/mL |
Comparison: Log-transformed plasma values were modeled using an ANOVA linear fixed-effect model with population (severe insufficiency, moderate insufficiency, and healthy control) as a fixed effect90% CI: [4.18, 7.22]
Comparison: Log-transformed plasma values were modeled using an ANOVA linear fixed-effect model with population (severe insufficiency, moderate insufficiency, and healthy control) as a fixed effect90% CI: [1.84, 3.18]
Primary
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.
Time frame: 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)
Population: Pharmacokinetic analysis was performed only for Part 2 data for participants in Part 2. Analysis was not conducted for Part 1, as review of drug concentration data, and dosing issues noted at investigative sites, indicated that in some participants, doses may not have been administered directly into vein, and likely infiltrated surrounding tissue.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Severe Renal Insufficiency Participants: Part 2 | 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 | 339 ug*hr/mL |
| Moderate Renal Insufficiency Participants: Part 2 | 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 | 151 ug*hr/mL |
| Healthy Control Participants: Part 2 | 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 | 62.5 ug*hr/mL |
Comparison: Log-transformed plasma values were modeled using an analysis of variance (ANOVA) linear fixed-effect model with population (severe insufficiency, moderate insufficiency, and healthy control) as a fixed effect90% CI: [4.12, 7.11]
Comparison: Log-transformed plasma values were modeled using an ANOVA linear fixed-effect model with population (severe insufficiency, moderate insufficiency, and healthy control) as a fixed effect90% CI: [1.84, 3.17]
Primary
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.
Time frame: 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)
Population: Pharmacokinetic analysis was performed only for Part 2 data for participants in Part 2. Analysis was not conducted for Part 1, as review of drug concentration data, and dosing issues noted at investigative sites, indicated that in some participants, doses may not have been administered directly into vein, and likely infiltrated surrounding tissue.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Severe Renal Insufficiency Participants: Part 2 | Geometric Least Squares Mean Maximum Observed Plasma Concentration (Cmax) Following a Single IV Dose of Sugammadex | 62.2 ug/mL |
| Moderate Renal Insufficiency Participants: Part 2 | Geometric Least Squares Mean Maximum Observed Plasma Concentration (Cmax) Following a Single IV Dose of Sugammadex | 60.6 ug/mL |
| Healthy Control Participants: Part 2 | Geometric Least Squares Mean Maximum Observed Plasma Concentration (Cmax) Following a Single IV Dose of Sugammadex | 66.1 ug/mL |
Comparison: Log-transformed plasma values were modeled using an ANOVA linear fixed-effect model with population (severe insufficiency, moderate insufficiency, and healthy control) as a fixed effect90% CI: [0.73, 1.21]
Comparison: Log-transformed plasma values were modeled using an ANOVA linear fixed-effect model with population (severe insufficiency, moderate insufficiency, and healthy control) as a fixed effect90% CI: [0.72, 1.18]
Primary
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.
Time frame: 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)
Population: Pharmacokinetic analysis was performed only for Part 2 data for participants in Part 2. Analysis was not conducted for Part 1, as review of drug concentration data, and dosing issues noted at investigative sites, indicated that in some participants, doses may not have been administered directly into vein, and likely infiltrated surrounding tissue.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Severe Renal Insufficiency Participants: Part 2 | Geometric Mean Apparent First-order Terminal Elimination Half-life (t1/2) Following a Single IV Dose of Sugammadex | 13.24 hr | Geometric Coefficient of Variation 35.5 |
| Moderate Renal Insufficiency Participants: Part 2 | Geometric Mean Apparent First-order Terminal Elimination Half-life (t1/2) Following a Single IV Dose of Sugammadex | 5.73 hr | Geometric Coefficient of Variation 29.79 |
| Healthy Control Participants: Part 2 | Geometric Mean Apparent First-order Terminal Elimination Half-life (t1/2) Following a Single IV Dose of Sugammadex | 2.47 hr | Geometric Coefficient of Variation 13.49 |
Primary
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.
Time frame: 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)
Population: Pharmacokinetic analysis was performed only for Part 2 data for participants in Part 2. Analysis was not conducted for Part 1, as review of drug concentration data, and dosing issues noted at investigative sites, indicated that in some participants, doses may not have been administered directly into vein, and likely infiltrated surrounding tissue.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Severe Renal Insufficiency Participants: Part 2 | Geometric Mean Apparent First-order Terminal Elimination Rate Constant (λz) Following a Single IV Dose of Sugammadex | 0.0524 1/hr | Geometric Coefficient of Variation 35.5 |
| Moderate Renal Insufficiency Participants: Part 2 | Geometric Mean Apparent First-order Terminal Elimination Rate Constant (λz) Following a Single IV Dose of Sugammadex | 0.121 1/hr | Geometric Coefficient of Variation 29.8 |
| Healthy Control Participants: Part 2 | Geometric Mean Apparent First-order Terminal Elimination Rate Constant (λz) Following a Single IV Dose of Sugammadex | 0.280 1/hr | Geometric Coefficient of Variation 13.5 |
Primary
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.
Time frame: 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)
Population: Pharmacokinetic analysis was performed only for Part 2 data for participants in Part 2. Analysis was not conducted for Part 1, as review of drug concentration data, and dosing issues noted at investigative sites, indicated that in some participants, doses may not have been administered directly into vein, and likely infiltrated surrounding tissue.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Severe Renal Insufficiency Participants: Part 2 | Geometric Mean Apparent Volume of Distribution Estimated at Steady-state (Vss) Following a Single IV Dose of Sugammadex | 15.1 L | Geometric Coefficient of Variation 19.7 |
| Moderate Renal Insufficiency Participants: Part 2 | Geometric Mean Apparent Volume of Distribution Estimated at Steady-state (Vss) Following a Single IV Dose of Sugammadex | 15.9 L | Geometric Coefficient of Variation 21.9 |
| Healthy Control Participants: Part 2 | Geometric Mean Apparent Volume of Distribution Estimated at Steady-state (Vss) Following a Single IV Dose of Sugammadex | 14.1 L | Geometric Coefficient of Variation 20.4 |
Primary
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.
Time frame: 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)
Population: Pharmacokinetic analysis was performed only for Part 2 data for participants in Part 2. Analysis was not conducted for Part 1, as review of drug concentration data, and dosing issues noted at investigative sites, indicated that in some participants, doses may not have been administered directly into vein, and likely infiltrated surrounding tissue.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Severe Renal Insufficiency Participants: Part 2 | Geometric Mean Effective Half-life (t1/2eff) Following a Single IV Dose of Sugammadex | 10.89 hr | Geometric Coefficient of Variation 26.15 |
| Moderate Renal Insufficiency Participants: Part 2 | Geometric Mean Effective Half-life (t1/2eff) Following a Single IV Dose of Sugammadex | 4.87 hr | Geometric Coefficient of Variation 30.84 |
| Healthy Control Participants: Part 2 | Geometric Mean Effective Half-life (t1/2eff) Following a Single IV Dose of Sugammadex | 1.72 hr | Geometric Coefficient of Variation 13.36 |
Primary
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.
Time frame: 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)
Population: Pharmacokinetic analysis was performed only for Part 2 data for participants in Part 2. Analysis was not conducted for Part 1, as review of drug concentration data, and dosing issues noted at investigative sites, indicated that in some participants, doses may not have been administered directly into vein, and likely infiltrated surrounding tissue.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Severe Renal Insufficiency Participants: Part 2 | Geometric Mean of Mean Residence Time (MRT) of Unchanged Drug in the Systemic Circulation Following a Single IV Dose of Sugammadex | 15.7 hr | Geometric Coefficient of Variation 26.2 |
| Moderate Renal Insufficiency Participants: Part 2 | Geometric Mean of Mean Residence Time (MRT) of Unchanged Drug in the Systemic Circulation Following a Single IV Dose of Sugammadex | 7.02 hr | Geometric Coefficient of Variation 30.8 |
| Healthy Control Participants: Part 2 | Geometric Mean of Mean Residence Time (MRT) of Unchanged Drug in the Systemic Circulation Following a Single IV Dose of Sugammadex | 2.48 hr | Geometric Coefficient of Variation 13.4 |
Primary
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.
Time frame: 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)
Population: Pharmacokinetic analysis was performed only for Part 2 data for participants in Part 2. Analysis was not conducted for Part 1, as review of drug concentration data, and dosing issues noted at investigative sites, indicated that in some participants, doses may not have been administered directly into vein, and likely infiltrated surrounding tissue.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Severe Renal Insufficiency Participants: Part 2 | Geometric Mean Percent of AUC0-∞ That Was Extrapolated (AUC%Extrap) Following a Single IV Dose of Sugammadex | 0.850 Percent extrapolated | Geometric Coefficient of Variation 43.5 |
| Moderate Renal Insufficiency Participants: Part 2 | Geometric Mean Percent of AUC0-∞ That Was Extrapolated (AUC%Extrap) Following a Single IV Dose of Sugammadex | 2.14 Percent extrapolated | Geometric Coefficient of Variation 29.2 |
| Healthy Control Participants: Part 2 | Geometric Mean Percent of AUC0-∞ That Was Extrapolated (AUC%Extrap) Following a Single IV Dose of Sugammadex | 2.10 Percent extrapolated | Geometric Coefficient of Variation 45.3 |
Primary
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-∞.
Time frame: 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)
Population: Pharmacokinetic analysis was performed only for Part 2 data for participants in Part 2. Analysis was not conducted for Part 1, as review of drug concentration data, and dosing issues noted at investigative sites, indicated that in some participants, doses may not have been administered directly into vein, and likely infiltrated surrounding tissue.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Severe Renal Insufficiency Participants: Part 2 | Geometric Mean Total Clearance (CL) Following a Single IV Dose of Sugammadex | 0.961 L/hr | Geometric Coefficient of Variation 26.8 |
| Moderate Renal Insufficiency Participants: Part 2 | Geometric Mean Total Clearance (CL) Following a Single IV Dose of Sugammadex | 2.27 L/hr | Geometric Coefficient of Variation 39.6 |
| Healthy Control Participants: Part 2 | Geometric Mean Total Clearance (CL) Following a Single IV Dose of Sugammadex | 5.70 L/hr | Geometric Coefficient of Variation 16 |
Primary
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).
Time frame: 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)
Population: Pharmacokinetic analysis was performed only for Part 2 data for participants in Part 2. Analysis was not conducted for Part 1, as review of drug concentration data, and dosing issues noted at investigative sites, indicated that in some participants, doses may not have been administered directly into vein, and likely infiltrated surrounding tissue.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Severe Renal Insufficiency Participants: Part 2 | Geometric Mean Volume of Distribution During the Terminal Elimination Phase (Vz) Following a Single IV Dose of Sugammadex | 18.3 L | Geometric Coefficient of Variation 24.8 |
| Moderate Renal Insufficiency Participants: Part 2 | Geometric Mean Volume of Distribution During the Terminal Elimination Phase (Vz) Following a Single IV Dose of Sugammadex | 18.8 L | Geometric Coefficient of Variation 24.2 |
| Healthy Control Participants: Part 2 | Geometric Mean Volume of Distribution During the Terminal Elimination Phase (Vz) Following a Single IV Dose of Sugammadex | 20.4 L | Geometric Coefficient of Variation 25.7 |
Primary
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.
Time frame: 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)
Population: Pharmacokinetic analysis was performed only for Part 2 data for participants in Part 2. Analysis was not conducted for Part 1, as review of drug concentration data, and dosing issues noted at investigative sites, indicated that in some participants, doses may not have been administered directly into vein, and likely infiltrated surrounding tissue.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Severe Renal Insufficiency Participants: Part 2 | Median Time of the Last Measurable Plasma Concentration (Tlast) Following a Single IV Dose of Sugammadex | 72.00 hr |
| Moderate Renal Insufficiency Participants: Part 2 | Median Time of the Last Measurable Plasma Concentration (Tlast) Following a Single IV Dose of Sugammadex | 24.00 hr |
| Healthy Control Participants: Part 2 | Median Time of the Last Measurable Plasma Concentration (Tlast) Following a Single IV Dose of Sugammadex | 12.00 hr |
Primary
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.
Time frame: 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)
Population: Pharmacokinetic analysis was performed only for Part 2 data for participants in Part 2. Analysis was not conducted for Part 1, as review of drug concentration data, and dosing issues noted at investigative sites, indicated that in some participants, doses may not have been administered directly into vein, and likely infiltrated surrounding tissue.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Severe Renal Insufficiency Participants: Part 2 | Median Time to Maximum Observed Plasma Concentration (Tmax) Following a Single IV Dose of Sugammadex | 0.03 hr |
| Moderate Renal Insufficiency Participants: Part 2 | Median Time to Maximum Observed Plasma Concentration (Tmax) Following a Single IV Dose of Sugammadex | 0.03 hr |
| Healthy Control Participants: Part 2 | Median Time to Maximum Observed Plasma Concentration (Tmax) Following a Single IV Dose of Sugammadex | 0.03 hr |