Clinical Report for Plavix - Case Study Example

Clinical Report for Plavix Introduction Plavix is an anti-platelet drug belonging to the group of drugs called Clopidogrel bisulfates, which are used to prevent clotting of platelets in the body and thus preventing unwanted blood clots in the heart, blood vessels and peripheral arterial systems. This drug is used prevent unwanted clots especially after recent cardiovascular events such as heart attacks and stroke. Clopidogrel belongs to a class of drugs referred to as anti-platelets. This drug is used to prevent heart attacks, stroke and other circulatory disorders in individuals who have had at least an episode of atherothrombotic event like heart disease, stroke as well as those diagnosed with peripheral arterial diseases characterized by problems with blood flowing into arteries especially in the leg region. This drug is also prescribed for patients diagnosed with acute coronary syndrome (ACS) and those with arterial fibrillation (AF); characterized by fast and irregular heartbeats (Dickie, Jennifer, and Lesley 34). Platelets are responsible for the clotting of blood whenever it is necessary for example, when one has a cut and in doing so prevents father bleeding and hemorrhage. In the event that arteries are narrowed by plagues, the body reacts by aggregating together and they may rapture and further increase narrowing of these vessels, which is, likely to increase the chance of heart attack, stroke and other circulatory disorders. This drug acts by reducing the chances of these occurrences by preventing the coagulation in the first place. Mechanism of Action Plavix acts by irreversibly binding to the P2Y12 receptors on platelets and preventing Adenosine diphosphate (ADP) from activating platelets, which form clots. Drug belongs to the group of drugs called P2Y12 inhibitors and is similar to the drug Ticlopidine (Ticlid) in its chemical structure and mechanism of action. The only difference is that Clopidogrel bisulfates do not cause serious decline in the white blood cell count as seen in patients on Ticlopidine hence there is no need for regular tests to determine white blood cell counts. Plavix is used to prevent the risk of heart disease and stroke in patients who have had a recent episode of heart attack, stroke and narrowed arteries as well as those suffering from peripheral vascular disease characterized by pain in the leg, which could be disabling. The US Food and Drug Association (FDA) approved this drug in 1997. Indication and Clinical use This drug is used in prevention of atherothrombotic events like myocardial infarction (MI), Stroke and vascular death in patients with atherosclerosis characterized by stroke, MI and established peripheral arterial disease. When combined with acetylsalicylic acid (ASA), it is used early and long term secondary prevention of atherothrombotic events in patients diagnosed with coronary syndromes without ST-segment elevation (Dickie et al p.411). This combination has proved beneficial for patients treated with a combination of ASA with other standard therapies. For example in patients who are being managed medically as well as those, being managed using percutaneous coronary intervention or coronary artery bypasses treatment. In patients found to have ST-segment elevation acute MI, studies have shown that this drug has is key to reducing the rate of death associated with heart disease, re-infarction or stroke (Dickie et al p.4010). In patients with arterial fibrillation (AF), and who have been found to possess at least one risk aspect for vascular events, who qualify for treatment with anticoagulants and with lowered risk of bleeding, this drug in combination with a low dosages of an ASA, is indicated to for deterrence of risky cardiovascular events like stroke (Dickie et al p.413). However, in patients with AF but with an increased risk of vascular events and able to tolerate Vitamin K antagonists given in VKA therapies, VKA has been shown to improve the clinical outcomes compared to administration of ASAs alone or even a combination of Plavix and ASA to minimize the event of stroke. The data about pediatrics is however undocumented. Dosage and Administration In MI, stroke and established arterial disease, the dosage given is 75mg daily with or without food (Dickie et al p.418). As for patients who are diagnosed with non-ST-segment elevation acute coronary syndrome (ACS) which includes those presenting with angina or non-Q-wave MI, Plavix administration is initiated with 300mg “loading” dose and then long-term dosage of 75mg every day combined with ASA 80-325 mg per day (Dickie et al p.421). Patients who have been found to have ST-segment elevation acute myocardial infarction (AMI) with or without and not on thrombolytics, Plavix is given 75 mg once per day in combination with ASA (Dickie et al p.432). There are no dosage adjustments for geriatric patients with renal impairment. In patients with AF plus presenting with a risk factor for vascular events but who have a low danger of bleeding but are not suitable for anticoagulant therapy, the recommended dosage is 75 mg once every day in combination with ASA 75-100mg per day. Individual who metabolize CYP2C19 poorly respond poorly to the antiplatelet function of clopidogrel. Higher doses regimen administered to otherwise healthy but poor metabolizing patients’ increases their response to antiplatelets but the right dosage for this type of patient population is yet to be established from clinical trials (Pfister p.100). When a dose is missed, it should be taken as soon as this is realized. However, if time of remembrance is close to the next dose, the missed dose is ignored and patient returns to their regular dosing schedule. An over dose is likely to result in prolonged bleeding time and risk of bleeding complications. In a study, a single dose of 1500-3000 mg/kg was shown to be lethal to rodents. However, there is no antidote for this but blood transfusion with platelets has been shown to reverse these pharmacological effects. Pharmacological Parameters of Plavix Pharmacokinetics Table 1. The main pharmacokinetics characteristics of Plavix Cmax T ½ (hrs) AUCo Single Dose Mean 2.19-2.50 ng/mL 6 2.7 ngh/L Clopidogrel is a pro-drug, which is metabolized to both active and inactive metabolites. Absorption Immediately after a single oral administration of the drug, it is rapidly absorbed and reaches the average plasma levels of about 2.19-2.50 ng/mL after about 45 minutes. Clopidogrel incorporation is at least half based on the urinary excretion of its metabolites. Distribution Clopidogrel and its inactive metabolite circulate in the blood and binds reversibly to human plasma protein in vitro at 98% to 94%, clopidogrel to clopidogrel metabolites respectively. The binding is not saturated in vitro until a concentration of 100ug/mL is reached. Metabolism Clopidogrel is metabolized through two metabolic pathways. One pathway is arbitrated by esterases results in the hydrolysis of this compound to an inactive carboxylic acid. This constitutes 85% of the absorbed clopidogrel. Multiple cytochrome P450 enzymes mediate the other pathway. Cytochrome is the oxidizer for clopidogrel to a 2-oxo-clopidogrel transitional metabolite, which is further metabolized to a thiol derivative, which is an active metabolite (Mason et al. 45). The CYP2C19, CYP3A, CYP2B6 and CYP1A2 mediate this metabolic pathway (Mason et al. 55). The thiol metabolite binds rapidly but irreversibly to platelet receptors and in doing so inhibit platelet coagulation during their lifespan. The Cmax of the dynamic metabolite is two times as high after a single 300mg loading dose compared to its concentration after 4 days of 75mg maintenance dose. Cmax is reached approximately 30-60 minutes post dosing. In the 75-300mg dosage range, clinical studies have shown that the pharmacokinetics of the dynamic metabolism deviates from dosage proportionally in that a four-fold increase in dosage results in 2.0-2.7 fold augment in Cmax and AUC. Elimination Clinical studies carried out by CURE indicate that following an oral dosage of clopidogrel that is labeled using carbon 14 in humans, roughly 50% and 46% of the total radioactivity was excreted through urine and stool respectively over 5 days post-administration. Clopidogrel has a half-life of about 6 hours while its active metabolite has the half-life of 30 minutes as seen after administration of Flavix 75mg. Pharmacodynamics Clopidogrel bisulfate is metabolized by CYP450 enzymes in the liver and converted to the active metabolite that hinders the coagulation of platelets in the vascular system. The active metabolites hinder the binding of ADP to the platelet P2Y12 receptor, preventing the ADP mediated activation of glycoprotein GPIIb/IIIa complex and in doing so, prevents platelet coagulation. This process is irreversible, these platelets exposed to Clopidogrel bisulfate, and its metabolites spend the rest of their lifespan (normally, 7-10 days) under their influence ensuring the maintenance of the vascular system. Dose-dependent reserve of platelet coagulation can be observed 2 hours after administering Plavix as a single oral dose. Repeated dosages of 75mg Plavix per day is enough to inhibit ADP-induced platelet coagulation on the first day of administering it and this inhibition reaches a steady state by day 3-7. At this steady state, the observed inhibition level on average was between 40-60% with the 75mg dosage daily. Platelet coagulation and bleeding time steadily returned to baseline values 5 days post discontinuing the drug. This effect was observed to be the same in geriatric patients, 75 years and above as well as in healthy pediatrics. In patients, strict renal mutilation (creatinine clearance rate of 5-15mL/min) and those with reasonable renal mutilation (creatinine clearance rate of 30-60 mL/min); the hindering of ADP-induced platelet coagulation was lower at about 25%. In patients with severe impairment of the hepatic system, repeated doses of 75mg/day Plavix for 10 days resulted in hindering of ADP-induced platelet coagulation that was comparable to that in healthy patients. In a study comparing gender differences and the relationship between gender and ADP-induced platelet coagulation inhibition, women had less inhibition compared to men. Pharmacogenomics According to ZUERN et al, it is CYP2C19 that participates in the configuration of both the dynamic metabolites of clopidogrel as well as 2-oxo-clopidogrel transitional metabolite. The pharmacokinetics and antiplatelet effects of the active clopidogrel metabolite is measured using ex vivo platelet comprehensive assays and these differ according to the CYP2C19 genotype. This genotype differences also affects configuration of clopidogrel dynamic metabolites. CYP2C19*1 is the allele that functions and fully corresponds to the functional metabolism while allele CYP2C19*2 and allele *3 are non functional. These non functional alleles are found in about 85% Caucasians and 99% Asians individuals who poorly metabolize clopidogrel. The alleles CYP2C19 *4,*5,*6,*7 and *8 are also associated with decreased metabolism but these are rare. Patients who are poor clopidogrel metabolism are found to have two a combination of any of the non functioning alleles above. Studies show that approximately 2% of Caucasians, 4% of blacks and 14% of Chinese poorly metabolise CYP2C19. In CURE, plavix use was seen to reduce the occurrence of MI, stroke and cardiovascular mortality in the study group but was dependent on the different characteristics of patients in terms of the therapies they were on such as heparin, lipid lowering drugs, beta blockers and inhibitors of ACE. However, the efficacy of Plavix in CURE was observed independent of the administered asprin. The study also excluded the use of other anti platelet coagulants, oral anticoagulant as well as long term NSAIDs. In CURE, use of Plavix was shown to decrease the use of thrombolytic therapy in about 71 patients or 1.1% of patients given the Plavix therapy as well as 126 or 12% of those being given a placebo. The calculated relative risk associated here was 43%. There was a decrease in use of GPIIb/IIIa inhibitors in 369 patients which represents 5.9% of the Plavix administered group and 454 patients or 7.2% in those on placebo group. This is representative of an 18% decreased relative risk. However, Plavix use in this study didn’t affect the relative risk in patients co treated with CABG/PCI that is 2253 patients or 36% in the Plavix study group and 2324 or 36.9% in control group meaning a decrease in relative risk by 4%. Drug Interactions The metabolism of Clopidogrel bisulfate to its active metabolites is partly done by CYP2C19 enzyme. Decrease in plasma concentration of the active metabolites is associated with concomitant use of some drugs which act by inhibiting this enzyme resulting in a decrease Plavix’s efficacy in platelet aggregation inhibition. These include Proton Pump Inhibitors (PPIs), anticoagulant drugs, food and herbs as well as other therapies associated with vascular disease treatment. The effect of PPIs on the blood’s exposure to Clopidogrel bisulfate active metabolites post multiple dosing with Plavix 75mg/day presented in figure 1 below. Figure1: Exposure to Clopidogrel Active Metabolites after repeated administration of Plavix 75mg/day alone with PPIs. Source: http://www.rxlist.com/plavix-drug/clinical-pharmacology.htm The pharmacodynamic and pharmacokinetic levels measured in the studies represented by Figure 1 above clearly indicated that the interaction was highest with omeprazole and lowest with dexlansoprazole. The interaction with anticoagulants is of great concern due to possible bleeding and these should be administered with great caution. Warfarin is a CYP2C9 substrate and high concentrations of Plavix in vitro inhibit its action. In patients on long-term Warfarin therapy, admission of Plavix 75mg/day did not affect its pharmacokinetics, but co-administration of Warfarin and Plavix, was observed to cause an increase in chances of bleeding due to their independent affects on homeostasis (Mason et al p.543-7). CURE clinical studies showed that there were no significant pharmacodynamic interactions observed when Plavix was administered together with atenolol, nifedipine either separately or in combination. Co-administration of Plavix and Phenobarbital enhanced pharmacodynamic activity of Plavix though quite slightly. It is however unlikely that Plavix interferes with the metabolism of Phenytoin, Tolbutamide and the anti-inflammatory drugs (NSAIDs) as these are metabolized by cytochrome P4502C9. There we no clinically adverse effects detected in clinical trials with Plavix where the patients received a variety of non-concomitant medications like ASAs, diuretics, angiotensin converting enzyme (ACE) inhibitors, calcium channel blockers, lipid-lowering agents, coronary vasodilators, insulin, thrombolytics and heparin. In CURE, patients on heparin or low molecular weight heparin (LMWH) and Plavix did not experience any increase in incidence of bleeding events. Use of Plavix and asprin resulted in increase in major events of bleeding in the GI tract compared to the administration of asprin on its own. The events of brain bleeding were estimated at 0.1% while bleeding that result in death was at 0.2% in both control and Plavix groups. Reports of primary epistaxis and hematuria also reported. There were no significant interactions between food and Plavix since administration of Plavix was not dependent of food intake. Interactions with herbs and spices were not established. Adverse Reactions The safety profile of Plavix was evaluated in clinical trials involving approximately 12,562 patients diagnosed with cases of acute coronary syndrome or ACS not in combination with ST-elevation who had in the past 24 hours experienced pain in the chest area. They had an ECG to establish presence of new stroke with non ST characteristics. The patient population consisted largely of Caucasians at 82% with 38% of them women with 52% being individuals aged over 65 years. They were scheduled to receive Plavix loading dose of 300mg then later 75mg to be administered daily for at least one year together with asprin 75 to 325 mg every day. The control group was given a placebo plus asprin 75 to 325 mg every day for a year. Other therapies like administration of heparin were continued although the administration of GPIIb/IIIa was paused for 3 days prior to the start of trials. 582 patients or 9.3% experienced cardiovascular compromise and death, MI and/or stroke in the Plavix administered group while 719 or 11.4% of the patients being given the placebo experienced these outcomes. This shows a 20% relative decrease in the risk. This represents 95%confidence interval of 11-29%; p1%) with or without ASA in controlled clinical trials were, hemorrhage and bleeding disorders including purpura, a rash, dyspepsia, abdominal pain and diarrhea. The most serious adverse drug reaction from the trials rarely reported ( Read More