Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

10.2    Pharmacodynamics
Cardiac Electrophysiology
At exposures at least 5 times higher than that of the recommended doses of RADICAVA, edaravone does not prolong the QT interval to any clinically relevant extent.

Pharmacokinetic Properties

10.3    Pharmacokinetics
RADICAVA is administered by IV infusion. The maximum plasma concentration (Cmax) of edaravone was reached by the end of infusion. There was a trend of more than dose proportional increase in area under the concentration-time curve (AUC) and Cmax of edaravone. With multiple-dose administration, edaravone does not accumulate in plasma.
Distribution
Edaravone is bound to human serum proteins (92%), mainly to albumin, with no concentration dependence in the range of 0.1 to 50 micromol/L. Edaravone has a mean volume     of    distribution  after    intravenous    administration    of    63.1     L.

Elimination
The mean terminal elimination half-life of edaravone is approximately 4.5 to 9 hours. The half- lives of its metabolites are 3 to 6 hours. Following intravenous administration, the total clearance of edaravone is estimated to be 35.9 L/h.
Metabolism
Edaravone is metabolized to a sulfate conjugate and a glucuronide conjugate, which are not pharmacologically active. The glucuronide conjugation of edaravone involves multiple uridine diphosphate glucuronosyltransferase (UGT) isoforms (UGT1A1, UGT1A6, UGT1A7, UGT1A8, UGT1A9, UGT1A10, UGT2B7, and UGT2B17). In human plasma, edaravone is mainly detected as the sulfate conjugate, which is presumed to be formed by sulfotransferases.
Excretion
In Japanese and Caucasian healthy volunteer studies, edaravone was excreted mainly in the urine as its glucuronide conjugate (60-80% of the dose up to 48 hours).
Approximately 6-8% of the dose was recovered in the urine as the sulfate conjugate, and < 1% of the dose was recovered in the urine as the unchanged drug. In vitro studies suggest that the 
sulfate conjugate of edaravone is hydrolyzed back to edaravone, which is then converted to the glucuronide conjugate in the kidney before excretion into the urine.
Specific Populations
Geriatric Patients
No age effect on edaravone pharmacokinetics has been found [see Use in Specific Populations (8.4)].
Patients with Renal Impairment
Following single IV infusion of 30 mg edaravone (half the recommended dosage of RADICAVA) over 60 minutes, mean Cmax and AUC0-∞ of unchanged edaravone were 1.15- and 1.20-fold greater in the subjects with mild renal impairment (eGFR 60-89 mL/min/1.73m2), and were 1.25- and 1.29-fold greater in the subjects with moderate renal impairment (eGFR 30-59 mL/min/1.73m2) when compared to subjects with normal renal function, respectively. These changes in exposures are not considered to be clinically significant and therefore no dosage adjustments are necessary in patients with mild to moderate renal impairment. The effects of severe renal impairment on the pharmacokinetics of edaravone have not been studied.
Patients with Hepatic Impairment
Following single IV infusion of 30 mg edaravone (half of the recommended dose of RADICAVA) over 60 minutes, mean Cmax and AUC0-∞ of unchanged edaravone were 1.20- and 1.07- fold greater in the subjects with mild hepatic impairment (Child-Pugh score 5 or 6), were 1.24- and 1.14-fold greater in the subjects with moderate hepatic impairment (Child-Pugh score 7 to 9), and were 1.20- and 1.19-fold greater in the subjects with severe hepatic impairment (Child-Pugh score 10 to 14) when compared to subjects with normal hepatic function, respectively. These changes in exposures are not considered to be clinically significant and therefore no dosage adjustments are necessary in patients with hepatic impairment.
Male and Female Patients
No gender effect on edaravone pharmacokinetics has been found.
Racial or Ethnic Groups
There were no significant racial differences in Cmax and AUC of edaravone between Japanese and Caucasian subjects.
Drug Interaction Studies
The pharmacokinetics of edaravone is not expected to be significantly affected by inhibitors of cytochrome P450 (CYP) enzymes, UGTs or major transporters.
In vitro studies demonstrated that, at the recommended dosage, edaravone and its metabolites are not expected to significantly inhibit CYP enzymes (CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A), conjugating enzymes UGT1A1 and UGT2B7, or other transporters (P-gp, OATP1B1, OATP1B3, OAT1, OCT2, MATE1, and MATE2-K) in humans. Edaravone and its metabolites are not expected to induce CYP1A2, or CYP2B6, at the recommended dosage of edaravone.
In vitro data indicated that edaravone was not a substrate of OATP1B1 or OATP1B3.