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.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
31
Inclisiran is a synthetic, chemically modified small interfering ribonucleic acid (siRNA) targeting proprotein convertase subtilisin kexin type 9 (PCSK9) messenger ribonucleic acid (mRNA) with a covalently attached triantennary N-acetylgalactosamine (GalNAc) ligand.
Auckland Clinical Studies Limited
Auckland, New Zealand
Christchurch Clinical Studies Trust
Christchurch, New Zealand
Pharmacokinetics: Maximum Observed Plasma Concentration (Cmax) Of Inclisiran
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.
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
Pharmacokinetics: Tmax And t1/2 Of Inclisiran
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.
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
Pharmacokinetics: AUC0-24, AUC0-48, And AUC0-inf Of Inclisiran
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.
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
Pharmacokinetics: Apparent Total Clearance (CL/F) Following SC Administration Of Inclisiran
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.
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
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Pharmacokinetics: Vd/F During The Terminal Elimination Phase Following SC Administration Of Inclisiran
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.
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
Pharmacokinetics: Amount Excreted Unchanged In Urine (Ae) Of Inclisiran Over 48 Hours Post-Dose
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.
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
Pharmacokinetics: Fraction Excreted (Fe) Of Inclisiran
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.
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
Pharmacokinetics: Renal Clearance (CLr) Of Inclisiran
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.
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
Change From Baseline In Lipids And Lipoproteins At Day 60
Pharmacodynamic effects of inclisiran on lipids and lipoproteins (total cholesterol, triglycerides, and high-density lipoprotein cholesterol, calculated and measured by beta-quant low-density lipoprotein cholesterol \[LDL-C\]) will be measured as a percentage of change from baseline. Lipids and lipoproteins will be measured at baseline, 4, 48, 96 (Day 4), and 168 (Day 7) hours, and Day 30 and Day 60.
Time frame: Baseline, Day 60
Change From Baseline In PCSK9 At Day 60
Pharmacodynamic effects of inclisiran on PCSK9 will be measured as a percentage of change from baseline. PCSK9 protein levels will be measured at baseline, 4, 48, 96 (Day 4), and 168 (Day 7) hours, and Day 30 and Day 60.
Time frame: Baseline, Day 60