Nowe doustne antykoagulanty szeroko dostępne – czas na stworzenie antidotów

Marzec 10, 2014  |  Udostępnij  | 

Nowe doustne antykoagulanty (NOAC), bezpośrednie inhibitory czynnika Xa (riwaroksaban i apiksaban) oraz inhibitor trombiny (dabigatran) powoli podbijają rynek farmaceutyczny. Ich głównym atutem, dla chorych nie do przecenienia, jest brak konieczności oznaczania wskaźnika INR. Niestety jednocześnie nie ma prostego badania laboratoryjnego, które pozwoliłoby ocenić stopień antykoagulacji osiągnięty u danego pacjenta, co może być szczególnie kłopotliwe w przypadkach przedawkowania tych leków. Poza tym problemem jest brak substancji, która odwracałby działanie NOAC. W przypadku ciężkiego krwawienia u chorego zatrutego inhibitorami czynnika Xa proponuje się próbę hemostazy chirurgicznej, przetoczenie świeżo mrożonego osocza lub podanie koncentratu kompleksu protrombiny. W przypadku przedawkowania dabigatranu można także podjąć próbę usunięcia krążącego we krwi leku za pomocą dializoterapii. Nie ma jednak badań naukowych, których wyniki potwierdzałyby skuteczność tych działań.

Jest jednak szansa, że opisany problem uda się wkrótce rozwiązać dzięki zsyntetyzowaniu specyficznej odtrutki. Wyniki badań nad antidotum nazwanym roboczo anexanet alfa zaprezentowano w trakcie dorocznego kongresu Amerykańskiego Towarzystwa Hematologicznego (ASH). Działanie opisywanej substancji jest możliwe dzięki podobieństwu jej cząsteczki do aktywowanego czynnika X. Dzięki temu krążące we krwi antykoagulanty, będące inhibitorami tego czynnika, są wiązane przez odtrutkę, a czynnik Xa pozostaje wolny, dzięki czemu może z powodzeniem brać udział w kaskadzie krzepnięcia. Molekuła leku jest dodatkowo tak spreparowana by sama w sobie nie wywoływała tworzenia skrzepliny. Obecnie anexanet alfa ma za sobą drugą fazę badań, czyli eksperyment na zdrowych ochotnikach. Protokół zakładał podawanie tym osobom przez 6 dni (poprzedzające podanie antidotum) inhibitorów czynnika Xa w dawkach zalecanych w migotaniu przedsionków, a następnie ocenę skuteczności i bezpieczeństwa stosowanej odtrutki. Uzyskane dane pokazały przewidywalny, zależny od dawki antidotum, spadek aktywności zarówno riwaroksabanu jak i apiksabanu, Po podaniu 720 mg preparatu anexanet w bolusie uzyskano odwrócenie antykoagulacji w 90% u blisko 70% chorych. Jednocześnie odnotowywano proporcjonalny spadek stężenia w osoczu niezwiązanego riwaroksabanu. Co ważne, u ponad 80 osób, na których antidotum było testowane, nie zaobserwowano żadnych poważnych działań niepożądanych, w tym powikłań zakrzepowo-zatorowych. Także poziomy markerów takich jak D-dimery, czy kompleksy trombina-antytrombina, mieściły się w granicach normy.

Na podobnym etapie zaawansowania są także badania mające na celu wprowadzenie na rynek farmaceutyczny preparatu odwracającego działanie dabigatranu. By skutecznie przywracać prawidłowe krzepnięcie u pacjentów przyjmujących ten lek, metodami biologii molekularnej wytworzono cząsteczkę, będącą w istocie fragmentem przeciwciała zbudowanego tak, by wiązać dabigatran, nie powodując przy tym reakcji układu odpornościowego. Tu także badania na zdrowych ochotnikach wykazały przewidywalne, zależne od dawki antidotum ograniczenie działania antykoagulacyjnego. Jednocześnie nie obserwowano zależnych od podania leku działań niepożądanych czy reakcji immunologicznych.

Wyniki badań nad oboma preparatami przedstawiają się obiecująco. Ze względów etycznych w przypadku antidotów nie przeprowadza się badań randomizowanych porównujących ich skuteczność z placebo, tak więc pomyślne wyniki badań II fazy stawiają omawiane specyfiki o krok od dopuszczenia do użytku klinicznego. Jednocześnie należy zauważyć, że chociaż przypadki ciężkich krwawień u pacjentów przyjmujących nowe doustne koagulanty są rzadsze niż wśród osób leczonych acenokumarolem, z pewnością nie zabraknie przypadków, w których podanie odpowiedniej odtrutki będzie oznaczało uratowanie życia. Z taką sytuacją możemy mieć do czynienia choćby u pacjentów przyjmujących NOAC i wymagających pilnej operacji w sytuacji nagłego zagrożenia zdrowia.


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