NCT02011490

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

Completed Phase 1 Results posted Last updated 2 October 2018

What this trial tests

Phase 1 trial testing sugammadex in Renal Insufficiency in 33 participants. Completed in 6 June 2014.

Timeline

11 December 2013

Primary endpoint
6 June 2014

6 June 2014

Quick facts

Lead sponsor	Merck Sharp & Dohme LLC
Phase	Phase 1
Status	Completed
Study type	INTERVENTIONAL
Allocation	non randomized
Design	parallel
Masking	none
Primary purpose	treatment
Enrollment	33
Start date	11 December 2013
Primary completion	6 June 2014
Estimated completion	6 June 2014
Sites	1 location across United States

Drugs / interventions tested

• sugammadex — full drug profile →

Conditions studied

• Renal Insufficiency — all drugs for Renal Insufficiency →
• Renal Impairment — all drugs for Renal Impairment →

Sponsor

Merck Sharp & Dohme LLC — full company profile →

Who can join

18 and older, any sex, with Renal Insufficiency or Renal Impairment. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

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 Primary · 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 port

Group	Value	95% CI
Severe Renal Insufficiency Participants: Part 2	339	268 – 428
Moderate Renal Insufficiency Participants: Part 2	151	120 – 191
Healthy Control Participants: Part 2	62.5	49.5 – 79.0

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 Primary · 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.

Group	Value	95% CI
Severe Renal Insufficiency Participants: Part 2	335	265 – 424
Moderate Renal Insufficiency Participants: Part 2	148	117 – 187
Healthy Control Participants: Part 2	61.1	48.3 – 77.3

Geometric Least Squares Mean Maximum Observed Plasma Concentration (Cmax) Following a Single IV Dose of Sugammadex Primary · 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.

Group	Value	95% CI
Severe Renal Insufficiency Participants: Part 2	62.2	50.2 – 77.1
Moderate Renal Insufficiency Participants: Part 2	60.6	49.0 – 75.1
Healthy Control Participants: Part 2	66.1	53.3 – 81.8

Geometric Mean Percent of AUC0-∞ That Was Extrapolated (AUC%Extrap) Following a Single IV Dose of Sugammadex Primary · 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.

Group	Value	95% CI
Severe Renal Insufficiency Participants: Part 2	0.850	± 43.5
Moderate Renal Insufficiency Participants: Part 2	2.14	± 29.2
Healthy Control Participants: Part 2	2.10	± 45.3

Geometric Mean Total Clearance (CL) Following a Single IV Dose of Sugammadex Primary · 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-∞.

Group	Value	95% CI
Severe Renal Insufficiency Participants: Part 2	0.961	± 26.8
Moderate Renal Insufficiency Participants: Part 2	2.27	± 39.6
Healthy Control Participants: Part 2	5.70	± 16.0

Geometric Mean Volume of Distribution During the Terminal Elimination Phase (Vz) Following a Single IV Dose of Sugammadex Primary · 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).

Group	Value	95% CI
Severe Renal Insufficiency Participants: Part 2	18.3	± 24.8
Moderate Renal Insufficiency Participants: Part 2	18.8	± 24.2
Healthy Control Participants: Part 2	20.4	± 25.7

Geometric Mean of Mean Residence Time (MRT) of Unchanged Drug in the Systemic Circulation Following a Single IV Dose of Sugammadex Primary · 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.

Group	Value	95% CI
Severe Renal Insufficiency Participants: Part 2	15.7	± 26.2
Moderate Renal Insufficiency Participants: Part 2	7.02	± 30.8
Healthy Control Participants: Part 2	2.48	± 13.4

Geometric Mean Apparent Volume of Distribution Estimated at Steady-state (Vss) Following a Single IV Dose of Sugammadex Primary · 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.

Group	Value	95% CI
Severe Renal Insufficiency Participants: Part 2	15.1	± 19.7
Moderate Renal Insufficiency Participants: Part 2	15.9	± 21.9
Healthy Control Participants: Part 2	14.1	± 20.4

Median Time to Maximum Observed Plasma Concentration (Tmax) Following a Single IV Dose of Sugammadex Primary · 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.

Group	Value	95% CI
Severe Renal Insufficiency Participants: Part 2	0.03	0.03 – 0.08
Moderate Renal Insufficiency Participants: Part 2	0.03	0.02 – 0.08
Healthy Control Participants: Part 2	0.03	0.03 – 0.08

Median Time of the Last Measurable Plasma Concentration (Tlast) Following a Single IV Dose of Sugammadex Primary · 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.

Group	Value	95% CI
Severe Renal Insufficiency Participants: Part 2	72.00	71.99 – 143.99
Moderate Renal Insufficiency Participants: Part 2	24.00	23.99 – 47.99
Healthy Control Participants: Part 2	12.00	11.99 – 12.00

Geometric Mean Apparent First-order Terminal Elimination Half-life (t1/2) Following a Single IV Dose of Sugammadex Primary · 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.

Group	Value	95% CI
Severe Renal Insufficiency Participants: Part 2	13.24	± 35.50
Moderate Renal Insufficiency Participants: Part 2	5.73	± 29.79
Healthy Control Participants: Part 2	2.47	± 13.49

Geometric Mean Effective Half-life (t1/2eff) Following a Single IV Dose of Sugammadex Primary · 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.

Group	Value	95% CI
Severe Renal Insufficiency Participants: Part 2	10.89	± 26.15
Moderate Renal Insufficiency Participants: Part 2	4.87	± 30.84
Healthy Control Participants: Part 2	1.72	± 13.36

Adverse events — posted to ClinicalTrials.gov

Time frame: Up to Day 35 (Part 1) or Day 14 (Part 2). Reporting threshold: 5%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Severe Renal Insufficiency Participants: Part 1

Serious: 0/8 (0%)

Deaths: —

Moderate Renal Insufficiency Participants: Part 1

Serious: 0/8 (0%)

Deaths: —

Healthy Control Participants: Part 1

Serious: 0/8 (0%)

Deaths: —

Severe Renal Insufficiency Participants: Part 2

Serious: 0/6 (0%)

Deaths: —

Moderate Renal Insufficiency Participants: Part 2

Serious: 0/6 (0%)

Deaths: —

Healthy Control Participants: Part 2

Serious: 0/6 (0%)

Deaths: —

Other adverse events (10 terms — click to expand)

Reaction	System	Severe Renal Insufficiency…	Moderate Renal Insufficien…	Healthy Control Participan…	Severe Renal Insufficiency…	Moderate Renal Insufficien…	Healthy Control Participan…
Paraesthesia oral	Gastrointestinal disorders	—	—	—	—	—	—
Injection site extravasation	General disorders	—	—	—	—	—	—
Injection site reaction	General disorders	—	—	—	—	—	—
Tooth infection	Infections and infestations	—	—	—	—	—	—
Contusion	Injury, poisoning and procedural complications	—	—	—	—	—	—
Muscular weakness	Musculoskeletal and connective tissue disorders	—	—	—	—	—	—
Pain in extremity	Musculoskeletal and connective tissue disorders	—	—	—	—	—	—
Dizziness	Nervous system disorders	—	—	—	—	—	—
Headache	Nervous system disorders	—	—	—	—	—	—
Hypoaethesia	Nervous system disorders	—	—	—	—	—	—

Data from ClinicalTrials.gov NCT02011490 adverse events section.

Sponsor's own description

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.

Publications & conference data

No peer-reviewed publications indexed yet for this trial. Completed trials usually publish results within 12-18 months.