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| __NOTOC__
| | #REDIRECT [[Abciximab#Pharmacology]] |
| {{Abciximab}}
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| {{CMG}}; {{AE}} {{SS}}, {{PB}}
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| ==Clinical Pharmacology==
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| ====General====
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| Abciximab binds to the intact platelet [[GPIIb/IIIa]] receptor, which is a member of the [[integrin]] family of adhesion receptors and the major platelet surface receptor involved in [[platelet aggregation]]. Abciximab inhibits platelet aggregation by preventing the binding of [[fibrinogen]], [[von Willebrand factor]], and other adhesive molecules to GPIIb/IIIa receptor sites on activated platelets. The mechanism of action is thought to involve steric hindrance and/or conformational effects to block access of large molecules to the receptor rather than direct interaction with the RGD ([[arginine]]-[[glycine]]-[[aspartic acid]]) binding site of GPIIb/IIIa.
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| Abciximab binds with similar affinity to the [[vitronectin]] receptor, also known as the α<sub>v</sub>β<sub>3</sub> integrin. The vitronectin receptor mediates the procoagulant properties of platelets and the proliferative properties of vascular endothelial and smooth muscle cells. In in vitro studies using a model cell line derived from [[melanoma]] cells, Abciximab blocked α<sub>v</sub>β<sub>3</sub>-mediated effects including cell adhesion (IC<sub>50</sub> = 0.34 μg/mL). At concentrations which, in vitro, provide > 80% GPIIb/IIIa receptor blockade, but above the in vivo therapeutic range, Abciximab more effectively blocked the burst of thrombin generation that followed platelet activation than select comparator antibodies which inhibit GPIIb/IIIa alone.
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| The relationship of these in vitro data to clinical efficacy is unknown.
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| Abciximab also binds to the activated [[Mac-1]] receptor on [[monocytes]] and [[neutrophils]]. In in vitro studies, Abciximab and 7E3 [[IgG]] blocked [[Mac-1]] receptor function as evidenced by inhibition of monocyte adhesion. In addition, the degree of activated [[Mac-1]] expression on circulating leukocytes and the numbers of circulating leukocyte-platelet complexes has been shown to be reduced in patients treated with Abciximab compared to control patients. The relationship of these in vitro data to clinical efficacy is uncertain.
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| ====Pre-clinical experience====
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| Maximal inhibition of [[platelet aggregation]] was observed when ≥ 80% of GPIIb/IIIa receptors were blocked by Abciximab. In non-human primates, Abciximab bolus doses of 0.25 mg/kg generally achieved a blockade of at least 80% of platelet receptors and fully inhibited platelet aggregation. Inhibition of platelet function was temporary following a bolus dose, but receptor blockade could be sustained at ≥ 80% by continuous intravenous infusion. The inhibitory effects of Abciximab were substantially reversed by the transfusion of platelets in monkeys. The antithrombotic efficacy of prototype antibodies [murine 7E3 Fab and F(ab´)2] and Abciximab was evaluated in dog, monkey and baboon models of coronary, carotid, and femoral artery [[thrombosis]]. Doses of the murine version of 7E3 or Abciximab sufficient to produce high-grade (≥ 80%) GPIIb/IIIa receptor blockade prevented acute [[thrombosis]] and yielded lower rates of [[thrombosis]] compared with [[aspirin]] and/or [[heparin]].
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| ====Pharmacokinetics====
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| Following intravenous bolus administration, free plasma concentrations of Abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second phase half-life of about 30 minutes, probably related to rapid binding to the platelet [[GPIIb/IIIa]] receptors. Platelet function generally recovers over the course of 48 hours (5,6), although Abciximab remains in the circulation for 15 days or more in a platelet-bound state. Intravenous administration of a 0.25 mg/kg bolus dose of Abciximab followed by continuous infusion of 10 μg/min (or a weight-adjusted infusion of 0.125 μg/kg/min to a maximum of 10 μg/min) produces approximately constant free plasma concentrations throughout the infusion. At the termination of the infusion period, free plasma concentrations fall rapidly for approximately six hours then decline at a slower rate.
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| ====Pharmacodynamics====
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| Intravenous administration in humans of single bolus doses of Abciximab from 0.15 mg/kg to 0.30 mg/kg produced rapid dose-dependent inhibition of platelet function as measured by ex vivo [[platelet aggregation]] in response to [[adenosine diphosphate]] (ADP) or by prolongation of [[bleeding time]]. At the two highest doses (0.25 and 0.30 mg/kg) at two hours post injection (the first time point evaluated), over 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation in response to 20 μM ADP was almost abolished. The median bleeding time increased to over 30 minutes at both doses compared with a baseline value of approximately five minutes.
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| Intravenous administration in humans of a single bolus dose of 0.25 mg/kg followed by a continuous infusion of 10 μg/min for periods of 12 to 96 hours produced sustained high-grade [[GPIIb/IIIa]] receptor blockade (≥ 80%) and inhibition of platelet function (ex vivo platelet aggregation in response to 5 μM or 20 μM ADP less than 20% of baseline and bleeding time greater than 30 minutes) for the duration of the infusion in most patients. Similar results were obtained when a weight-adjusted infusion dose (0.125 μg/kg/min to a maximum of 10 μg/min) was used in patients weighing up to 80 kg. Results in patients who received the 0.25 mg/kg bolus followed by a 5 μg/min infusion for 24 hours showed a similar initial receptor blockade and inhibition of [[platelet aggregation]], but the response was not maintained throughout the infusion period. The onset of Abciximab-mediated platelet inhibition following a 0.25 mg/kg bolus and 0.125 μg/kg/min infusion was rapid and platelet aggregation was reduced to less than 20% of baseline in 8 of 10 patients at 10 minutes after treatment initiation.
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| Low levels of [[GPIIb/IIIa]] receptor blockade are present for more than 10 days following cessation of the infusion. After discontinuation of Abciximab infusion, platelet function returns gradually to normal. Bleeding time returned to ≤ 12 minutes within 12 hours following the end of infusion in 15 of 20 patients (75%), and within 24 hours in 18 of 20 patients (90%). Ex vivo platelet aggregation in response to 5 μM ADP returned to ≥ 50% of baseline within 24 hours following the end of infusion in 11 of 32 patients (34%) and within 48 hours in 23 of 32 patients (72%). In response to 20 μM ADP, ex vivo platelet aggregation returned to ≥ 50% of baseline within 24 hours in 20 of 32 patients (62%) and within 48 hours in 28 of 32 patients (88%).<ref name="dailymed.nlm.nih.gov">{{Cite web | last = | first = | title = REOPRO (ABCIXIMAB) INJECTION, SOLUTION [ELI LILLY AND COMPANY] | url = http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=033d4c3b-4630-4256-b8f7-9ed5f15de9a3#nlm34067-9 | publisher = | date = | accessdate = }}</ref>
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| ==References==
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| {{Reflist}}
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| {{FDA}}
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| [[Category:Drugs]]
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