A Single-Dose, Open-Label, Parallel-Group Study to Assess the Pharmacokinetics of Inclisiran in Subjects With Renal Impairment Compared to Subjects With Normal Renal Function (ORION-7)
Overview
- Phase
- Phase 1
- Intervention
- Inclisiran
- Conditions
- Renal Impairment
- Sponsor
- The Medicines Company
- Enrollment
- 31
- Locations
- 2
- Primary Endpoint
- Pharmacokinetics: Tmax And t1/2 Of Inclisiran
- Status
- Completed
- Last Updated
- 7 years ago
Overview
Brief Summary
This study is a Phase I, single-dose, open-label trial to evaluate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics of a single dose of inclisiran subcutaneous (SC) injection in participants with mild, moderate, and severe renal impairment compared to participants with normal renal function.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Male and female participants 18 to 80 years of age
- •Participants should be qualified for inclusion based upon estimated CrCl ranges for normal renal function group and mild, moderate, and severe renal impairment groups
Exclusion Criteria
- •Participants with acute renal disease and/or history of renal transplant
- •Urinary incontinence without catheterization
- •Participants requiring hemodialysis
- •Participants with LDL-C \<60 mg/deciliter (dL) (or less than 1.55 millimoles/liter \[mmol/L\])
- •Participants with Amyloid Kidney (if known by pathology)
- •Participants with any significant hepatic, cardiac, or pulmonary disease or participants who are clinically nephritic
- •The above information is not intended to contain all considerations relevant to a participant's potential participation in a clinical trial.
Arms & Interventions
Inclisiran (normal renal function)
Participants will receive a single dose of 300 milligram (mg) inclisiran administered by SC injection on Day 1. Normal renal function is defined as estimated creatinine clearance (CrCl) of ≥90 milliliter (mL)/minute (min).
Intervention: Inclisiran
Inclisiran (mild renal impairment)
Participants will receive a single dose of 300 mg inclisiran administered by SC injection on Day 1. Mild renal impairment is defined as CrCl ranging from 60 to 89 mL/min.
Intervention: Inclisiran
Inclisiran (moderate renal impairment)
Participants will receive a single dose of 300 mg inclisiran administered by SC injection on Day 1. Moderate renal impairment is defined as CrCl ranging from 30 to 59 mL/min.
Intervention: Inclisiran
Inclisiran (severe renal impairment)
Participants will receive a single dose of 300 mg inclisiran administered by SC injection on Day 1. Severe renal impairment is defined as CrCl ranging from 15 to 29 mL/min.
Intervention: Inclisiran
Outcomes
Primary Outcomes
Pharmacokinetics: Tmax And t1/2 Of Inclisiran
Time Frame: 0 (pre-dose), 0.5, 1, 2, 4, 6, 8, 12, 24, and 48 hours post-dose and Day 4, Day 7, Day 14, and Day 30 post dose
Measurement of effect of renal impairment on PK of inclisiran by assessment of time to reach maximum plasma concentration (Tmax) and time for inclisiran to reach half of its initial value (t1/2). Serial blood samples will be collected for the analysis. PK parameters will be determined from the plasma concentration-time profiles using a noncompartmental approach.
Pharmacokinetics: AUC0-24, AUC0-48, And AUC0-inf Of Inclisiran
Time Frame: 0 (pre-dose), 0.5, 1, 2, 4, 6, 8, 12, 24, and 48 hours post-dose and Day 4, Day 7, Day 14, and Day 30 post dose
Measurement of effect of renal impairment on PK of inclisiran by assessment of area under the curve of the plasma concentration (AUC) from time 0 to 24 hours (AUC0-24), from time 0 to 48 hours (AUC0-48), and from time 0 extrapolated to infinity (AUC0-inf). Serial blood samples will be collected for the analysis. PK parameters will be determined from the plasma concentration-time profiles using a noncompartmental approach.
Pharmacokinetics: Maximum Observed Plasma Concentration (Cmax) Of Inclisiran
Time Frame: 0 (pre-dose), 0.5, 1, 2, 4, 6, 8, 12, 24, and 48 hours post-dose and Day 4, Day 7, Day 14, and Day 30 post-dose
Measurement of effect of renal impairment on PK of inclisiran by assessment of Cmax. Serial blood samples will be collected for the analysis. PK parameters will be determined from the plasma concentration-time profiles using a noncompartmental approach.
Pharmacokinetics: Vd/F During The Terminal Elimination Phase Following SC Administration Of Inclisiran
Time Frame: 0 (pre-dose), 0.5, 1, 2, 4, 6, 8, 12, 24, and 48 hours post-dose and Day 4, Day 7, Day 14, and Day 30 post dose
Measurement of effect of renal impairment on PK of inclisiran by assessment of apparent volume of distribution (Vd/F) of inclisiran during the terminal elimination phase. Serial blood samples will be collected for the analysis. PK parameters will be determined from the plasma concentration-time profiles using a noncompartmental approach.
Pharmacokinetics: Renal Clearance (CLr) Of Inclisiran
Time Frame: 0 up to 6 hours, 6 up to 12 hours, 12 up to 24 hours, and 24 up to 48 hour post-dose intervals
Measurement of effect of renal impairment on PK of inclisiran by assessment of CLr, calculated as Ae/AUC0-48 plasma. CLr will be calculated if possible (for example, if the percent of unchanged drug excreted in urine exceeds 20%). Pooled urine samples will be used for the analysis.
Pharmacokinetics: Fraction Excreted (Fe) Of Inclisiran
Time Frame: 0 up to 6 hours, 6 up to 12 hours, 12 up to 24 hours, and 24 up to 48 hour post-dose intervals
Measurement of effect of renal impairment on PK of inclisiran by assessment of the urinary recovery rate over a specific collection interval (Fe), calculated as 100\*Ae/Dose. Pooled urine samples will be used for the analysis.
Pharmacokinetics: Apparent Total Clearance (CL/F) Following SC Administration Of Inclisiran
Time Frame: 0 (pre-dose), 0.5, 1, 2, 4, 6, 8, 12, 24, and 48 hours post-dose and Day 4, Day 7, Day 14, and Day 30 post dose
Measurement of effect of renal impairment on PK of inclisiran by assessment of CL/F. Serial blood samples will be collected for the analysis. PK parameters will be determined from the plasma concentration-time profiles using a noncompartmental approach.
Pharmacokinetics: Amount Excreted Unchanged In Urine (Ae) Of Inclisiran Over 48 Hours Post-Dose
Time Frame: 0 up to 6 hours, 6 up to 12 hours, 12 up to 24 hours, and 24 up to 48 hour post-dose intervals
Measurement of effect of renal impairment on PK of inclisiran by assessment of Ae of inclisiran. Pooled urine samples will be used for the analysis.
Secondary Outcomes
- Change From Baseline In Lipids And Lipoproteins At Day 60(Baseline, Day 60)
- Change From Baseline In PCSK9 At Day 60(Baseline, Day 60)