JAKAFI
JAKAFI jest lekiem, którego składnikiem aktywnym jest fosforan ruxolitinibu. Lek produkowany jest przez firmę INCYTE CORP, która w listopadzie 2011 otrzymała zgodę na jego sprzedaż od amerykańskiej Agencji ds Żywności i Leków (FDA USA). Lek ten może być stosowany w leczeniu łagodnego lub też zaawansowanego zwłóknienia szpiku (mielofibrozy), zarówno pierwotnego, jak i wtórnego (bedącego powikłaniem czerwienicy prawdziwej lub nadpłytkowości samoistnej. Dostępny jest w formie doustnych tabletek (po 5, 10, 15, 20, albo 25 mg składnika aktywnego). Do poważniejszych powikłań stosowania leku JAKAFI zaliczyć można:
- mielosupresję (anemia, małopłytkowość, neutropenia),
- ryzyko infekcji (bakteryjnych, wirusowych, grzybiczych).
[Image:JAKAFI-Rysunek1.png|frame|Struktura chemiczna ruxolitinibu]
Mechanizm działania
Ruxolitinib phosphate is a kinase inhibitor with the chemical name (R)-3-(4-(7H-pyrrolo[2,3 d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropanenitrile phosphate and a molecular weight of 404.36. Ruxolitinib phosphate has the following structural formula Ruxolitinib phosphate is a white to off-white to light pink powder and is soluble in aqueous buffers across a pH range of 1 to 8. Ruxolitinib, a kinase inhibitor, inhibits Janus Associated Kinases (JAKs) JAK1 and JAK2 which mediate the signaling of a number of cytokines and growth factors that are important for hematopoiesis and immune function. JAK signaling involves recruitment of STATs (signal transducers and activators of transcription) to cytokine receptors, activation and subsequent localization of STATs to the nucleus leading to modulation of gene expression. Myelofibrosis (MF) is a myeloproliferative neoplasm (MPN) known to be associated with dysregulated JAK1 and JAK2 signaling. In a mouse model of JAK2V617F-positive MPN, oral administration of ruxolitinib prevented splenomegaly, preferentially decreased JAK2V617F mutant cells in the spleen and decreased circulating inflammatory cytokines (eg, TNF-α, IL-6). Ruxolitinib inhibits cytokine induced STAT3 phosphorylation in whole blood from healthy subjects and MF patients. Jakafi administration resulted in maximal inhibition of STAT3 phosphorylation 2 hours after dosing which returned to near baseline by 10 hours in both healthy subjects and myelofibrosis patients.
Absorption
In clinical studies, ruxolitinib is rapidly absorbed after oral Jakafi administration with maximal
plasma concentration (Cmax) achieved within 1 to 2 hours post-dose. Based on a mass balance
study in humans, oral absorption of ruxolitinib was estimated to be at least 95%. Mean
ruxolitinib Cmax and total exposure (AUC) increased proportionally over a single dose range of
5 to 200 mg. There were no clinically relevant changes in the pharmacokinetics of ruxolitinib
upon administration of Jakafi with a high-fat meal, with the mean Cmax moderately decreased
(24%) and the mean AUC nearly unchanged (4% increase).
Distribution
The apparent volume of distribution of ruxolitinib at steady-state is 53 to 65 L in myelofibrosis
patients. Binding to plasma proteins in vitro is approximately 97%, mostly to albumin.
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Reference ID: 3412646
Metabolism
In vitro studies suggest that CYP3A4 is the major enzyme responsible for metabolism of
ruxolitinib. Ruxolitinib is the predominant entity in humans representing approximately 60% of
the drug-related material in circulation. Two major and active metabolites were identified in
plasma of healthy subjects representing 25% and 11% of parent AUC. These two metabolites
have one-fifth and one-half of ruxolitinib’s pharmacological activity, respectively. The sum total
of all active metabolites contributes 18% of the overall pharmacodynamics of ruxolitinib.
Elimination
Following a single oral dose of [14C]-labeled ruxolitinib in healthy adult subjects, elimination
was predominately through metabolism with 74% of radioactivity excreted in urine and 22%
excretion via feces. Unchanged drug accounted for less than 1% of the excreted total
radioactivity. The mean elimination half-life of ruxolitinib is approximately 3 hours and the
mean half-life of ruxolitinib + metabolites is approximately 5.8 hours.
http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/202192s005lbl.pdf