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虫号: 1120936
注册: 2010-10-12
性别: GG
专业: 药剂学

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Pharmacokinetics

Non-clinical pharmacokinetic studies were conducted mainly in Wistar rats and dogs. Toxicokinetic
data were collected from repeated dose studies in mice (CD-1), rats, dogs and female rabbits. General
organ distribution was studied in Wistar rats and pigmented rats; placental transfer and excretion into
milk was studied in female Wistar rats. Plasma protein binding and metabolism were investigated in
vitro  in  several  species,  including  Cynomolgus  monkeys  and  humans.  Several in  vitro  studies  were conducted to characterise the involvement, inhibition and induction of cytochrome Ps (CYPs), P-gp and Bcrp. Finally, cell permeability was studied in Caco-2 cells.
Absorption  after  a  single  oral  dose  of  rivaroxaban  was  rapid  in  both  rats  and  dogs  with  maximal plasma concentration achieved in about 0.5 hours. The extent of absorption was somewhat lower in rats (67%) than in dogs (92%). After repeat dosing for 4 weeks, there was an increased absorption in rats, but not in mice or dogs. Higher exposure was observed in the female rats.
Protein  binding  varied  between  species,  highest  being  in  rat  (98.7%)  and  lowest  in  rabbit  (76.6%). Mechanistic studies showed that serum albumin is the main binding protein. However, a mechanistic study with human serum albumin (HSA) and oleic acid showed a striking difference in protein binding depending on the oleic acid concentration. This difference in protein binding is large enough to cover almost the entire range observed in different species.
Organ distribution after a single oral dose of rivaroxaban shows highest concentrations in the gastro-
intestinal  tract,  liver  and  kidneys,  lower  concentrations  in  the  brain.  Rivaroxaban  showed  minor affinity  to  melanin-containing  tissues,  such  as  pigmented  skin  areas  and  eyes.  After  repeated  oral administration  to  rats  (14  consecutive  daily  administrations),  radioactivity  showed  a  moderate accumulation  tendency.  A  slow  elimination  of  rivaroxaban  and  its  metabolites  from  bone  after repeated dosing raised a suspicion of a potential connection with skeletal malformations observed in the reproductive toxicity studies. However, the detailed review of the data revealed that the absolute retention  in  bone  is unlikely  to  prolong  exposure  and  thus  cause  adverse  effects  on  skeleton.
Nevertheless, the embryotoxic observation (see section on Toxicology) remains and is addressed in the
SPC. Volume of distribution was moderate, amounting to 0.3 L/kg for the rat and to 0.4 L/kg for the
dog.  Rivaroxaban  was  eliminated  from  rat  and  dog  plasma  with  half-lives  between  1  and  2  h.
Rivaroxaban passes through the placental barrier but does not accumulate in the foetuses. In rats, the
substance is excreted in milk.
Rivaroxaban  is subject  to oxidative  metabolism  in  liver.  The  in vivo  biotransformation  pathways  of rivaroxaban in man are similar to those in animals and are reflected in the in vitro investigation with liver microsomes and cultured hepatocytes from different species. The main metabolic pathway, the oxidative degradation of the morpholinone moiety, was catalyzed by CYP3A4/3A5 and CYP2J2 and lead  via  cleavage  of  the  ring  and  further  oxidation  to  the  formation  of  metabolite  M1.  Another pathway  is  the  hydrolysis  of  the  amide  bond,  generating  metabolites  M15  and  M13.  Besides unchanged rivaroxaban, metabolite M1 was identified as main metabolite in the excreta of animals and man. Qualitatively, the animal metabolism of rivaroxaban is similar to that of man and there are no unique human metabolites. There are quantitative differences but none of them represent a cause for concern.
Elimination of rivaroxaban from plasma was rapid with no major circulating metabolites detected in
plasma of rat, dog, and man. The main excretion routes in the investigated animal species and in man
were  renal  and  faecal/biliary.  The  rat  differs  from  dogs  and  humans  by  a  higher  proportion  of rivaroxaban and metabolites excreted in bile/faeces, and a lower proportion excreted in urine.

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