ed mean ± SD steady state peak concentrations (Cmax), trough concentrations (Ctrough), and areaunder the curve (AUCτ) were 7.15 ± 2.14 µg/mL, 0.021 ± 0.044 µg/mL, and 184 ± 159 µg·h/mL, respectively.
Theaccumulation of AUCτ was 3.2-fold at steady state, compared to the first dose. In the placebo-controlled study, interpatientvariability in patisiran exposuredidnot result in differences in clinical efficacy (mNIS+7 change from baseline) orsafety (adverse events, serious adverse events).
Distribution
Plasma protein binding of ONPATTRO is low, with ≤2.1% binding observed in vitro with human serum albumin andhuman α1-acid glycoprotein. ONPATTRO distributes primarily to the liver. At the recommended dosing regimen of0.3 mg/kg every 3 weeks, the mean ± SD steady state volume of distribution of patisiran (Vss) was 0.26 ± 0.20 L/kg.
Elimination
The terminal elimination half-life (mean ± SD) of patisiran is 3.2 ± 1.8 days. Patisiran is mainly cleared throughmetabolism, and the total body clearance (mean ± SD) at steady state (CLss) is 3.0 ± 2.5 mL/h/kg.
Metabolism
Patisiran is metabolized by nucleases to nucleotides of various lengths.
Excretion
Less than 1% of the administered dose of patisiran is excreted unchanged into urine.
Specific Populations
Age, race (non-Caucasian vs. Caucasian), and sex had no impact on the steady state pharmacokinetics of patisiran or TTRreduction. Population pharmacokinetic and pharmacodynamic analyses indicated no impact of mild or moderate renalimpairment (eGFR ≥30 to <90 mL/min/1.73m2) or mild hepatic impairment (bilirubin ≤1 x ULN and AST >1 x ULN, orbilirubin >1.0 to 1.5 x ULN) on patisiran exposure or TTR reduction. ONPATTRO has not been studied in patients withsevere renal impairment, end-stage renal disease, moderate or severe hepatic impairment, or in patients with prior livertransplant.
Drug Interaction Studies
No formal clinical drug interaction studies have been performed. The components of ONPATTRO are not inhibitors orinducers of cytochrome P450 enzymes or transporters. Patisiran is not a substrate of cytochrome P450 enzymes. In apopulation pharmacokinetic analysis, concomitant use of strong or moderate CYP3A inducers and inhibitors did not impact the pharmacokinetic parameters of patisiran. ONPATTRO is not expected to cause drug-drug interactions or to be
affected by inhibitors or inducers of cytochrome P450 enzymes.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis
Patisiran-LC was not carcinogenic in TgRasH2 mice when administered at intravenous (IV) doses of 0, 0.5, 2, or 6 mg/kg
every two weeks for 26 weeks.
Mutagenesis
Patisiran-LC was negative for genotoxicity in in vitro (bacterial mutagenicity assay, chromosomal aberration assay inhuman peripheral blood lymphocytes) and in vivo (mouse bone marrow micronucleus) assays.
Impairment of Fertility
Intravenous (IV) administration of patisiran-LC (0, 0.03, 0.1, or 0.3 mg/kg) or a rodent-specific (pharmacologicallyactive) surrogate (0.1 mg/kg) to male rats every two weeks prior to and throughout mating to untreated females producedno adverse effects on fertility.
Intravenous administration of patisiran-LC (0, 0.15, 0.50, or 1.5 mg/kg) or a rodent-specific (pharmacologically act |
