Study of Pharmacokinetics of a Single IV Dose of CB-238,618 in Subjects With Varying Degrees of Renal Impairment Compared to Healthy Subjects (MK-6183-001)

Healthy Volunteers Clinical Trial

Official title:

A Phase 1, Non-randomized, Parallel-group, Open-label Study to Characterize the Pharmacokinetics of a Single Intravenous Dose of CB-238,618 in Subjects With Varying Degrees of Renal Impairment Compared to Healthy Subjects

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02341599
• Other study ID #: 6183-001
• Secondary ID: 618-REN-14-02MK-
• Status: Completed
• Phase: Phase 1
• Start date: December 11, 2014
• Est. completion date: April 20, 2015

Study information

• Verified date: February 2019
• Source: Cubist Pharmaceuticals LLC
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The purpose of this study is to characterize the effect of renal function on the plasma, urine, and dialysate pharmacokinetic profile of MK-6183 (CB-238,618) in humans. The study will also assess the safety profile and tolerability of MK-6183 in healthy participants, participants with varying degrees of renal impairment (RI), or participants with end-stage renal disease (ESRD) requiring hemodialysis (HD), based on estimated glomerular filtration rate (eGFR).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 40
• Est. completion date: April 20, 2015
• Est. primary completion date: April 13, 2015
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Participants who are healthy; or who have mild, moderate, or severe RI; or who have ESRD requiring HD. Participants with ESRD requiring HD should have been receiving HD 3 times per week for at least 3 months preceding the initial dose in this study

Exclusion Criteria:

• For healthy participants (Group A): history or presence of any clinically significant illness (e.g., cardiovascular, pulmonary, hepatic, renal, hematologic, gastrointestinal, endocrine, immunologic, dermatologic, neurologic, oncologic, musculoskeletal, or psychiatric) or any other condition, including clinically significant anemia, which in the opinion of the investigator would jeopardize the safety of the participant or the validity of the study results

• For participants with RI (Groups B to E): as above, except that RI and other medical conditions commonly associated with renal impairment (eg, hypertension, diabetes, which should be stable for at least three months preceding the initial dose of study medication in this study) are allowed

• Clinically significant abnormalities on physical examination, medical history, 12-lead electrocardiogram (ECG), vital signs, or laboratory values, as judged by the investigator or designee. Subjects with renal impairment should have clinical laboratory values consistent with their disease and approved by the investigator

• Evidence of clinically significant hepatic impairment including alanine aminotransferase or aspartate aminotransferase >1.5 × upper limit of normal (ULN) or bilirubin >1 × ULN

• Hemoglobin <8 g/dL, unless considered stable and not clinically significant in the opinion of the investigator in subjects with ESRD and on HD

• Participants with renal impairment who are not on a chronic stable drug regimen, defined as starting a new drug or changing dosage within 14 days prior to administration of study medication, except for drugs administered in relationship to HD

• Participants with fluctuating or rapidly deteriorating renal function (assessment of the stability of the subject's renal function will be determined by the investigator)

• Participant has a currently functioning renal transplant and/or has been on significant immunosuppressant therapy, as determined by the investigator, within the last 6 months

Related Conditions & MeSH terms

• Healthy Volunteers
• Renal Impairment
• Renal Insufficiency

Intervention

Drug:
• MK-6183
MK-6183 (CB-238,614) is supplied as lyophilized powder 500 mg vial and mixed into solution for 100 mL intravenous (IV) administration over 1 hour.

Locations

Country	Name	City	State
n/a

Sponsors (1)

Lead Sponsor	Collaborator
Cubist Pharmaceuticals LLC

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Area Under the Plasma Concentration-time Curve (AUC) From Dosing to Last Measurable Concentration (AUC0-last) of MK-6183	AUC0-last is the area under the plasma concentration-time curve from the time of dosing to the last post-dose measurable concentration. Blood samples for Group E were collected both prior to and during HD (Period 1) and after HD (Period 2) [data from Periods 1 and 2 were analyzed separately]. In Period 1, HD commenced 3.5 hours post-dose (HD duration was 3.5 to 4 hours) and sample collection continued until 48 hours post-dose. The specific time frame of plasma sample collection for Group E: Period 1 was pre-dose, 0.5 hours post-dose, EOI, 1.5 hours post-dose, 2 hours post-dose, 3 hours post-dose (pre-HD), 3.5 hours post-dose with HD, 5 hours post-dose with HD, pre-end of HD, 30 min post-HD, 1 hour post-HD, 2 hours post-HD, 12 hours post-dose, 24 hours post-dose, and 48 hours post-dose.	Groups A to D & Group E: Period 2: Pre-dose and 0.5, 1 (end of infusion; EOI), 1.5, 2, 3, 6, 12, 24, 48, and 72 hours post-dose
Primary	AUC From Dosing to 8 (AUC0-8) of MK-6183	AUC0-8 is the extrapolated area under the plasma concentration-time curve from the time of dosing to infinity. Blood samples for Group E were collected both prior to and during HD (Period 1) and after HD (Period 2) [data from Periods 1 and 2 were analyzed separately]. In Period 1, HD commenced 3.5 hours post-dose (HD duration was 3.5 to 4 hours) and sample collection continued until 48 hours post-dose. The specific time frame of plasma sample collection for Group E: Period 1 was pre-dose, 0.5 hours post-dose, EOI, 1.5 hours post-dose, 2 hours post-dose, 3 hours post-dose (pre-HD), 3.5 hours post-dose with HD, 5 hours post-dose with HD, pre-end of HD, 30 min post-HD, 1 hour post-HD, 2 hours post-HD, 12 hours post-dose, 24 hours post-dose, and 48 hours post-dose. For statistical analyses, Group A is the reference and least squares (LS) mean ratios for tests (Groups B to E) are calculated as test/reference; Group E: Period 1 and Group E: Period 2 were also compared.	Groups A to D & Group E: Period 2: Pre-dose and 0.5, EOI, 1.5, 2, 3, 6, 12, 24, 48, and 72 hours post-dose
Primary	Maximum Plasma Drug Concentration (Cmax) of MK-6183	Cmax is the maximum observed post-dose drug concentration in plasma. Blood samples for Group E were collected both prior to and during HD (Period 1) and after HD (Period 2) [data from Periods 1 and 2 were analyzed separately]. In Period 1, HD commenced 3.5 hours post-dose (HD duration was 3.5 to 4 hours) and sample collection continued until 48 hours post-dose. The specific time frame of sample collection for Group E: Period 1 was pre-dose, 0.5 hours post-dose, EOI, 1.5 hours post-dose, 2 hours post-dose, 3 hours post-dose (pre-HD), 3.5 hours post-dose with HD, 5 hours post-dose with HD, pre-end of HD, 30 min post-HD, 1 hour post-HD, 2 hours post-HD, 12 hours post-dose, 24 hours post-dose, and 48 hours post-dose. For statistical analyses, Group A is the reference and LS mean ratios for tests (Groups B to E) are calculated as test/reference; Group E: Period 1 and Group E: Period 2 were also compared.	Groups A to D & Group E: Period 2: Pre-dose and 0.5, EOI, 1.5, 2, 3, 6, 12, 24, 48, and 72 hours post-dose
Primary	Apparent Total Body Clearance of MK-6183 From Plasma (CL)	CL is a measure of the clearance of drug from plasma via metabolism and excretion. Blood samples for Group E were collected both prior to and during HD (Period 1) and after HD (Period 2) [data from Periods 1 and 2 were analyzed separately]. In Period 1, HD commenced 3.5 hours post-dose (HD duration was 3.5 to 4 hours) and sample collection continued until 48 hours post-dose. The specific time frame of plasma sample collection for Group E: Period 1 was pre-dose, 0.5 hours post-dose, EOI, 1.5 hours post-dose, 2 hours post-dose, 3 hours post-dose (pre-HD), 3.5 hours post-dose with HD, 5 hours post-dose with HD, pre-end of HD, 30 min post-HD, 1 hour post-HD, 2 hours post-HD, 12 hours post-dose, 24 hours post-dose, and 48 hours post-dose.	Groups A to D & Group E: Period 2: Pre-dose and 0.5, EOI, 1.5, 2, 3, 6, 12, 24, 48, and 72 hours post-dose
Primary	Volume of Distribution at Steady State (Vss) of MK-6183	Vss is the apparent volume of distribution at steady state for MK-6183. Blood samples for Group E were collected both prior to and during HD (Period 1) and after HD (Period 2) [data from Periods 1 and 2 were analyzed separately]. In Period 1, HD commenced 3.5 hours post-dose (HD duration was 3.5 to 4 hours) and sample collection continued until 48 hours post-dose. The specific time frame of sample collection for Group E: Period 1 was pre-dose, 0.5 hours post-dose, EOI, 1.5 hours post-dose, 2 hours post-dose, 3 hours post-dose (pre-HD), 3.5 hours post-dose with HD, 5 hours post-dose with HD, pre-end of HD, 30 min post-HD, 1 hour post-HD, 2 hours post-HD, 12 hours post-dose, 24 hours post-dose, and 48 hours post-dose.	Groups A to D & Group E: Period 2: Pre-dose and 0.5, EOI, 1.5, 2, 3, 6, 12, 24, 48, and 72 hours post-dose
Primary	Apparent Plasma Half-life (t½) of MK-6183	t½ is the amount of time required for the plasma concentration of MK-6183 to reduce by 50%. Blood samples for Group E were collected both prior to and during HD (Period 1) and after HD (Period 2) [data from Periods 1 and 2 were analyzed separately]. In Period 1, HD commenced 3.5 hours post-dose (HD duration was 3.5 to 4 hours) and sample collection continued until 48 hours post-dose. The specific time frame of sample collection for Group E: Period 1 was pre-dose, 0.5 hours post-dose, EOI, 1.5 hours post-dose, 2 hours post-dose, 3 hours post-dose (pre-HD), 3.5 hours post-dose with HD, 5 hours post-dose with HD, pre-end of HD, 30 min post-HD, 1 hour post-HD, 2 hours post-HD, 12 hours post-dose, 24 hours post-dose, and 48 hours post-dose.	Groups A to D & Group E: Period 2: Pre-dose and 0.5, EOI, 1.5, 2, 3, 6, 12, 24, 48, and 72 hours post-dose
Primary	Cumulative Amount of MK-6183 Excreted in Urine or Dialysate (Ae)	Ae is the cumulative amount of drug excreted unchanged in urine or dialysate. For Groups A, B, C, and D, Ae was assessed in urine. For Group E: Period 1, Ae was assessed in dialysate (participants in Group E had no detectable urine data) at hourly collection intervals during HD (HD commenced 3 hours after dosing).	Groups A to D (urine): 0 to 24, 24 to 48, and 48 to 72 hours post-dose; Group E (dialysate): 0 to 1, 1 to 2, 2 to 3, and 3 to 4 hours after starting HD
Primary	Renal Clearance of MK-6183 (CLr)	CLr is the clearance of drug from plasma via the kidneys. Only data from Groups A, B, C, and D is presented; participants in Group E (Period 1) had no detectable urine data. Data for Group E: Period 1 are presented below in the dialysate clearance measure.	0 to 24, 24 to 48, and 48 to 72 hours post-dose
Primary	Dialysate Clearance of MK-6183 (CLd)	CLd is the amount of drug cleared from plasma via dialysis. Only data collected during HD (Group E: Period 1) is presented (HD commenced 3 hours after dosing).	0 to 1, 1 to 2, 2 to 3, and 3 to 4 hours after starting HD
Primary	Fraction of the Administered Dose of MK-6183 Excreted Unchanged in Urine or Dialysate (Fe)	Fe is the fraction (percentage) of the administered dose that was excreted unchanged in urine (Groups A to D) or dialysate (Group E: Period 1; HD commenced 3 hours after dosing).	Groups A to D (urine): 0 to 24, 24 to 48, and 48 to 72 hours post-dose; Group E (dialysate): 0 to 1, 1 to 2, 2 to 3, and 3 to 4 hours after starting HD
Secondary	Number of Participants Experiencing an Adverse Event (AE)	An AE is any untoward medical occurrence in a participant administered a pharmaceutical product that does not necessarily have to have a causal relationship with this treatment.	Up to 12 days
Secondary	Number of Participants Discontinuing From the Study Due to an AE	An AE is any untoward medical occurrence in a participant administered a pharmaceutical product that does not necessarily have to have a causal relationship with this treatment.	Up to 12 days