CENTER FOR DRUG EVALUATION AND
RESEARCH
APPLICATION NUMBER:
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204410Orig1s000
SUMMARY REVIEW
Cross Discipline Team Leader Review除夕之夜作文400字
allocation. The primary reviewer recommends that macitentan be labeled for the potential for
testicular toxicity (like bontan and ambrintan) and I concur.
Red Blood Cell Parameters
Do-related, reversible decreas in hematocrit, RBC, and hemoglobin concentration were
obrved in most rat and dog studies.
Reproductive Toxicity
There were generally no effects obrved on male and female fertility, although there was an
incread incidence of early intrauterine deaths and post-implantation loss on dames mated to
expod male rats.
Fetal developmental effects were evaluated in rats and rabbits. Serious malformations were
obrved at all dos tested and comprid craniofacial abnormalities and cardiovascular
abnormalities. The NOAEL for embryo-fetal development was not established for either宠物狗狗
species.
Other toxicology findings:
There was no evidence of genotoxicity or mutagenicity obrved with macitentan. The
carcinogenicity studies were considered negative by the Executive Carcinogenicity
Asssment Committee (CAC).
4.Clinical Pharmacology/Biopharmaceutics
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Pharmacokinetics
The pharmacokinetics of macitentan is do proportional from 1 to 30 mg. Cmax is reached by
about 8 hours after oral dosing. One active metabolite (ACT-132577-with less potency on the
ET A receptor and ET B receptor compared to macitentan) and one inactive metabolite (ACT-
373989) were studied(veral other inactive metabolites were identified). Macitentan and its
active metabolite are highly protein bound(the metabolite less so than the parent). Macitentan
undergoes metabolism by CYP3A and to a minor extent by CYP2C19. The apparent
elimination half-life of macitentan and its active metabolite are approximately16 and 48恍惚是什么意思
笔开头的成语hours, respectively. When radiolabeled drug is administered to healthy subjects, approximately
50% is recovered in urine and about 24% is recovered in feces.
There is no effect of food on absorption of the drug. Age, x, body weight and race had no
significant effect on exposure. Renal and hepatic impairment affect exposure (incread
exposure in renal impairment and decread exposure in hepatic impairment), but the changes
are not considered clinically significant and do not require do adjustment. Of note, patients
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with moderate to vere hepatic impairment were not studied in the pivotal trial.
Drug interactions
In vitro studies demonstrate that macitentan, at therapeutic dos, would not be susceptible to
drug interactions via P-glycoprotein, OATP, or CYP enzymes, other than CYP3A.
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