Ethics and Evidence in Clinical Trials - Assignment Example

Pharmacology study By The study aims at investigating possible interactions between thenew drug (JP234) and warfarin when they are administered in the treatment of patients with arterial fibrillation. The administration of JP234 an oral antiarrhythmic agent is utilized in heart rate control in atrial fibrillation. The administration of the drug among patients with cardiac arrhythmias has proved to be effective in prevention of arterial fibrillation. The effect of the new drug on the action of warfarin will be investigated in 20 healthy volunteers. The study type is interventional and will utilize randomized controlled design. Healthy participants will be assigned to group A and B. subjects in group A were given 50mg of JP234 from day 3 to day 10 and warfarin 1.5 mg from day 7 to day 14. Participants in group 2 will receive 1.5 mgs of warfarin from day 3 to 10 and then 50mgs once a day from day 7 to 14. Both drugs will be administered for the first fourteen days while the remaining six days will be utilized as washout period. Plasma levels of the drugs will be assessed in both groups. Monitoring the plasma concentration is essential in drug interaction studies. The subjects will be closely monitored for heart activity, clotting factor level and heart rate through utilization of an electrocardiogram. The drug is believed to be well tolerated during clinical trials and has less contraindication association with it (Simon, 2007). The result of the finding will be utilized in identifying the action of the new drug on the metabolism of warfarin. Through blood sample study and the hearts activity measure, the effectiveness and the action of JP234 on warfarin will be measured. The study aims at finding out the effect of JP234 on the action of warfarin. Any changes on the participants will be recorded. Tolerability and the safety of the drug will be assessed too. Background JP234 is well tolerated during clinical trials and there is no contradiction associated with it. The drug when administered is effective in doses of 50, 75 or 100mg once daily. The drug is metabolized in the liver and has a half life of about 24 hours. In vitro studies indicate that the drug can induce CYP2C9. Patients with chronic atrial fibrillation should be anticoagulated to hinder thromboembolism from taking place (Goodman, 2005). Patient taking JP234 are recommended to take warfarin that is partly metabolized by CYP2C9. JP234 is an antiarrhythmic drug and is usually excreted in the liver just the same as warfarin. The new drug is considered an inducer of CYP2C9 which takes part in the metabolism of warfarin. Before a drug is marketed to be utilized, its effectiveness should be outlined through well controlled and adequate clinical studies. A controlled study aims at exposing the population to the new agent with an intention of identifying the effects presented by the new agent such as concomitant therapy, placebo effect and spontaneous agent. The following parts of controls can be identified, historical control, dose-comparison concurrent control, placebo concurrent control and no treatment concurrent control (Doering et al, 1987). Drug interaction between the new drug and warfarin will also be tested. Testing for drug interaction is done with the efficacy and safety in mind. Investigation is done before marketing is done. The study aimed at investigating the potential of JP234 to induce the metabolism of a single dose of warfarin. Warfarin is a widely utilized anticoagulant and is considered highly efficacious. Its metabolism however varies on various therapeutic responses. Both in vitro and in vivo studies show conflicting findings on clinical relevance of cytochrome P450. The enzyme metabolizes both R and S warfarin into 6-, 7 and eight hydroxywarfarin. The new drug induces the enzyme unlike other antiarrhythmic drugs such as amiodarone which inhibit the enzyme. The metabolism of S- warfarin is considered less efficient than R-warfarin. Metabolic clearance of S and R enantiomers is done through oxidative reactions that are catalyzed by CYP2C9. The enzyme efficiently catalyzes S- warfarin (Morselli, 1974). Method The type of study utilized in the investigation will be randomized controlled design. Twenty adults of above 18 years old will be recruited as the study subjects with cardiac arrest problems. (Stockley, 1999). The participants will be randomly selected. The study will proceed after approval from the hospital of choice. The blood samples will be collected and tested for clotting factors. The study design is effective in studies targeting drugs. Subject selection and study protocol The subjects or participant in the study include the patients who are suffering from arterial fibrillation and are under medication. The study design will be utilized in studying the drug interaction between JP234 and warfarin in the selected patients. The patients or participants will be placed into two separate groups. The first group will be given the standard treatment whereas the other group will be offered the proposed drug. The study findings will indicate which regimen is effective and will measure the drug interaction by utilizing the drug samples. The participant to be offered the proposed drug and the one to be accorded the standard regimen will be selected randomly (Morselli, 1974). The participant selected should volunteer and consent to be used as study subjects. Eligibility Participants selected will be between eighteen to fifty years. Both genders are eligible for the study and volunteers who consent to the study will be selected. Inclusion criteria Healthy female and male non smoking subjects with body mass index of 18.0 to 32.0 kg/m2 and of age 18 to 50 years will be included in the study. Volunteers with hematocrit levels of around 36% and above will be selected. Exclusive criteria Patients with any chronic or acute medical condition will be excluded from the study. Patients with a history of palpitations will be excluded from the study and those with cardiac diseases of clinical relevance. Participants with less than 18 years will be excluded from the study. Patients with thromboembolic disorders will also be excluded from the study. Dose and schedule of JP234 The drug is considered effective in the doses of 50, 75 and 100mg it is offered once in a day. It has a half life of 24 hours and is administered orally. The antiarrhythmic drug is administered once in a day (Harkness, 1984). The maximum dosage that can be taken is 100 mgs in a day. Dose of warfarin schedule The control group will utilize 1.5 mg of warfarin while the other participants will be given JP234 and warfarin. Information and reactions should be taken before, during and after the treatment. The dosage of warfarin depends on INR values. Overdosing causes bleeding while under dosing results to thrombus formation (Serlin & Breckenridge, 2009). The maximum dose taken is 10mgs in a day. Procedure The effect of the new drug on the action of warfarin was investigated in 20 volunteers. Both warfarin and JP234 were administered among half of the subjects while the other half were considered as control experiment and took oral warfarin. The subjects will receive warfarin (1 mg daily) and JP234 (50mg daily) that will be co administered for twenty (20) days. Serum levels of warfarin are to be measured before, during and after JP234 administration at 8.30 a.m and on trail days at 11. 30 a.m, 3 hours after morning medication. Blood samples of JP234 will be collected and its active metabolites identified. INR levels will be utilized in ensuring safe use of warfarin. The subjects will be closely monitored for heart activity, clotting factor level and heart rate through utilization of an electrocardiogram (Harkness, 1984). Investigations Investigations will focus on the electrocardiogram monitor results and the blood sample collected. Plasma concentrations of both warfarin and JP234 will be collected among the subjects and recorded for analysis. Liver functional tests can also be performed to measure to measure the activities with regards to metabolism of both drugs among the subjects. INR levels will be used to monitor the safety of warfarin as it is being administered with JP234 (Serlin & Breckenridge, 2009). The peak plasma concentration of both drugs will be calculated in both groups to identify any interaction among the drugs encountered during absorption. Tmax will represent the maximum concentration of the drug in blood plasma while Cmax will measure the concentration after intake at steady state. Pharmacokinetic and pharmacodynamic parameters All pharmacological studies will be based on plasma concentration. The maximum plasma concentration will be determined by calculating the area under the concentration time curve. The time frame of the study will be twenty days. A curve of metabolism between both drugs will be drawn and used to calculate the concentration. Tmax is the time representing the maximum concentration of the drugs in plasma while Cmax will measure the concentration following the drug intake at steady state. Collection of other physical parameters and adverse events will be done assess the safety. The values will be measured from blood sample collected. The blood sample will also be used to monitor the action of both drugs (Harkness, 1984). Discussions Absorption Both warfarin and JP234 are oral drugs. R- Warfarin is less potent while S- warfarin is more potent and rapidly eliminated. Warfarin is absorbed well in the gut and has a hundred percent bioavailability. The half life of warfarin is 36- 42 hours and its metabolism takes place in the liver same to JP234 (Somberg, 2010). Both drugs will be administered orally and plasma concentration at steady state taken. The results will help determine any interaction that will influence the absorption of the drug. Metabolism Warfarin is often administered as a mixture of both R- and S – warfarin. The enantiomers are metabolized by different CYP enzymes. S- Warfarin metabolism is mainly done by CYP2C9 enzyme with CYP2C18, CYP2C19, CYP2C8 and CYP3A4/5 considered as minor pathway in the metabolism process. JP234 is considered an inducer of CYP2C9 and therefore tend to influence the action of the enzyme on Warfarin (Verma, 2010). The study will study the action of the new drug on Warfarin through study of the serum levels, blood levels and bile. The effect on S- warfarin metabolism will result to variability in the dosage requirement of the drug. The mode of action warfarin is based on its impact on the vitamin K synthesis. The action of the new drug on warfarin will also impact on the Vitamin K action. Metabolism of warfarin drug takes place as a result of oxidation. Both enantiomers are metabolized to metabolites of hydrowarfarin. . JP234 often induce CYP2C9 that has a high S-warfarin metabolic efficiency. The new drug therefore may have an impact on the metabolism of warfarin especially the S-enantiomers type. The drug interaction taste can be determined based on Km Values. The findings will also be based on bioavailability and plasma concentration of both warfarin and JP234 (Serlin & Breckenridge, 2009). Elimination Terminal half-life of warfarin after a single dose is usually one week while the half life of JP234 is twenty fur hours (Langier et al, 2009). The effective warfarin half-life range is however 20-60 hours with an average of 40 hours. S- Warfarin clearance is twice compared to R- warfarin. The half –life of S-warfarin is shorter than that of R- warfarin. Most of the oral warfarin drugs is recovered in Urine with less eliminated unchanged. Both JP234 and warfarin are metabolized in the liver and excreted in urine. The study will be able to identify the effect of drug interaction on elimination of warfarin. Distribution Warfarin distribution phase occurs within 6- 12 hours with 0.14L/kg as an appropriate volume of distribution. The drug will be administered orally in the study. In vitro and in vivo studies have indicated that warfarin binds to blood plasma proteins. Small fraction of it is however unbound and non available for therapeutic use (Serlin & Breckenridge, 2009). The narrow therapeutic window of warfarin and its ability to cause bleeding if overdosed and thrombus if under dozed calls for regular monitoring. International normalized ration (IRN) Effective use of warfarin can be able to control coagulation problems experienced by patient with arterial fibrillation. Warfarin treatment can be effectively monitored by checking the IRN levels. International normalized ration (IRN) testing plays an important role in warfarin treatment. IRN help in prevention of warfarin overdose and underdose. IRN result in addition to result interpretation can help manage the patient on the drug. Warfarin IRN normal range is between 2.0 to 3.0. Above 3.0 bleeding may occur while less than 2.0 thromboembolic state occurs. Patient taking warfarin should be tested regularly for IRN levels (Serlin & Breckenridge, 2009). Participants will be informed of the warning signs of bleeding or thrombus formation and should be able to report it to the medical practitioners in charge. The target of warfarin is 2.5 with a target range of between 2.0 TO 3.0. Utilization of warfarin in the treatment of arterial fibrillation should be conducted for indefinite period of time. Dosing calendars are of essence in the stipulated treatment. The participant should adhere to treatment regimen and avoid alcohol intake during the study period (Vann, 2011). The IRN level can be monitored to help identify any influence of JP234 on warfarin since IRN can be affected by drug interaction. When the IRN value is above 5, warfarin administration should be stopped and should be restarted when the level goes below five. Collection of blood sample Blood sample can be collected from the participants to test for plasma and blood level after administration (Hayakawa, 2011). The peak plasma levels can also be identified and measured and recorded. The collection of the samples and tests should be conducted by trained practitioners. Both in vitro and in vivo studies can be conducted after administration of the drug and warfarin. Liver enzyme test can be conducted and the drug interaction between the two drugs can be identified and recorded. A blood sample will measure the half life of the drugs at a given time. Blood test is considered to be an accurate way of determining whether the person has been intoxicated. Such tests are to be conducted by qualified personnel (Hay, 2009). The blood sample collected from the participants will be utilizing in confirming the half life of the new drug. Identifying the drug interaction is essential approach toward determining the safety of the drug. One drug can affect the activity of the other in the human body resulting to side effects that cannot be effectively tolerated. Identifying the negative effects of drug interaction can help change the way drugs are administered with the safety of the patient in mind. Drugs such as warfarin are associated with dangerous side effectives if not well administered. Health providers should therefore monitor the effects of the drugs very closely with an intention of preventing complications such as stroke that can easily cause death (Jolobe, 2006). New drugs such as JP234 therefore require to be taken through the various tests to test for its efficacy and safety in addition to drug interactions. Washout period The participants taking part in the study will be followed for twenty days. The half life of JP234 is twenty four hours while that one of warfarin has an average of fourty hours. The drugs will be administered in the first fourteen days with the rest six days utilized as washout period. Washout period is 5 times the half-life of the drug. Various tests including the INR will be conducted after the washout period to ensure the participants are safe. The diagram represents an investigative study design Initial recruitment. The study will take ten days followed by a two days wash out period excluded from the study Included and randomized (n=20) Group 1 n=10 The participants will be given warfarin 1 mg/day at 8. 30 a.m followed by JP234 50mg/day for 14 days. Warfarin will be administered based on INR levels. Blood sampled will be collected on 9th and 11th day three hours after administration of the drugs for the first 14 days followed by a washout period of six days. The study participants will be closely monitored The blood sample will be taken on 9th and 11th day for the first 14 days followed by a washout period of six days. The participants will be monitored closely during the study period. Conclusion The finding of the study will investigate the drug interactions of JP234 and warfarin. The result obtained will help determined the efficacy and pharmacokinetics of the drugs (Harkness, 1984). The tests targeting the participant will help identify the safety of the drug when it is administered together with anticoagulant such as warfarin. Patients with abnormal electrical conductivity of the heart often suffer from thromboembolic event, hence the need to utilize both the anticoagulant and antiarrhythmic drug in the management of the condition. Drug interactions can worsen the side effects and the health providers are requested to monitor the heart activity after such drugs have been administered especially with others. References Doering, W., Maass, L., Irmisch, R., & Konig, E. 1987. Pharmacokinetic interaction study with ramipril and digoxin in healthy volunteers. The American journal of cardiology, 59(10), D60-D64 Goodman, S. 2005. Ethics and evidence in clinical trials. Clinical Trials, 195-196. Harkness, R. 1984. Drug interactions handbook. Englewood Cliffs, N.J.: Prentice-Hall. Hay, G. 2009. Drug interactions with warfarin. Reactions, 11-12. Hayakawa, K. 2011. Evaluation of drug effect of antiarrhythmic agents. a. Guideline of evaluation of effect of antiarrhythmic agents. Rinsho Yakuri/Japanese Journal of Clinical Pharmacology and Therapeutics, 413-414. Jolobe, O. 2006. A perspective on antiarrhythmic drug therapy. American Heart Journal, E17-E17. Karl, J. 1996. The antiarrhythmic treatment of atrial fibrillation. Drug and Therapeutics Bulletin, 41-45. Langier, G., Marinchak, R., Rials, S., & Kowey, P. 2009. Antiarrhythmic drug interactions. Current Opinion in Cardiology, 26-28. Morselli, P. 1974. Drug interactions. New York: Raven Press. Obach, R. 2010. Drug-drug interactions: An important negative attribute in drugs. Drugs of Today, 301-301. Serlin, M., & Breckenridge, A. 2009. Drug Interactions with Warfarin. Drugs, 610-620. Simon, R. 2007. New challenges for 21st century clinical trials. Clinical Trials, 167-169. Somberg, J. 2010. Antiarrhythmic Drug Therapy. Cardiology, 329-348. Stockley, I. 1999. Drug interactions: A source book of adverse interactions, their mechanisms, clinical importance and management (5th ed.). London: Pharmaceutical Press. Vann, A. 2011. Clinical trials ... A caregivers recommendations. Clinical Trials, 679-679. Verma, K. 2010. Base of a Research: Good Clinical Practice in Clinical Trials. Journal of Clinical Trials. Read More