When PD variability is high and PK variability is low, the value of PK monitoring is not useful. No use, distribution or reproduction is permitted which does not comply with these terms. Wilcoxon signed-rank test was performed for comparison two by two (basal and TTR 4 weeks; basal and TTR 412 weeks; and, basal and TTR 12 weeks); all p-values were p < 0.001. J. Thromb. doi: 10.2146/sp150039, Feinberg, W. M., Blackshear, J. L., Laupacis, A., Kronmal, R., and Hart, R. G. (1995). In contrast, cyclosporine,[3739] phenytoin[40, 41] and procainamide[42] are and exemplify drugs with a direct PKPD relationship where the PK intersubject variability between patients is relatively high. All authors have contributed substantially to the conception and design of this paper. Venous blood samples were collected in tubes containing sodium citrate 3.8%. In addition, a Brazilian study showed that the patients achieved an adequate TTR after the pharmacist-driven management (64.3%) (de Lima Silva et al., 2017). However, because of their inherent toxicity, these drugs are used only in specialized settings by trained personnel whose knowledge and training substantially improves the riskbenefit ratio to the patient. 
It is not intended to describe a magnitude, such as narrow or wide. The Surgeon Generals Call to Action to Prevent Deep Vein Thrombosis and Pulmonary Embolism. In addition, we compared the antepenultimate, penultimate and last INR before the prospective phase of the study, as well as the INR at 4 and 12 weeks after protocol start. For full access to this pdf, sign in to an existing account, or purchase an annual subscription. Pharmacol. Pharm. Therefore, our findings could not be similar for new-diagnosed and general patients. In 2010, it was estimated that there are 33.5 million people in the world with AF (Feinberg et al., 1995; Chugh et al., 2014; Shantsila and Lip, 2016). First, the ideal design of an interventional study is the randomized control trial.
In addition, patients older than 80 years have 515% increased prevalence of AF (Camm et al., 2010). One objective of drug regulation is to obtain a favourable risk/benefit ratio based on the condition being treated and the duration of treatment. To summarize, it is this concept of a concentrationresponse curve and its delineation during drug development that we believe is at the heart of the Narrow Therapeutic Index issue. Benefit of oral anticoagulant over antiplatelet therapy in atrial fibrillation depends on the quality of international normalized ratio control achieved by centers and countries as measured by time in therapeutic range. Res.
Cardiovasc. The results of this investigation, summarized in Supplementary Table 1, indicate that both Narrow Therapeutic Index and Narrow Therapeutic Range, and their variants, are used to almost the same extent in the literature. J. Clin. However, in 1954 it was approved for medical use in the USA. a retrospective study of 2300 consecutive patients with venous thromboembolism. Also, the FDA published a list of NTI in November 1995 in the Guidance for Industry for Immediate Release Solid Oral Dosage From and better known as SUPAC-IR (Supplementary Appendix 1; https://www.fda.gov/regulatory-information/search-fda-guidance-documents/supac-ir-immediate-release-solid-oral-dosage-forms-scale-and-post-approval-changes-chemistry). Haemost. doi: 10.1007/s11096-016-0403-5, Wan, Y., Heneghan, C., Perera, R., Roberts, N., Hollowell, J., Glasziou, P., et al. This definition is more practical as it does not rely upon LD50 values and is based on the clinical experience with the drug. (2008). It may even increase the risk of death. This paper was part of the team at the Food and Drug Administration (FDA) that was formed in 1997 as at the time of Generic drug application for warfarin. Ann. However, at the recent Canadian Expert Advisory Committee on Bioavailability and Bioequivalence meeting held in March 2001,[29] the Narrow Therapeutic Index drugs, referred to as critical drugs were defined as: Comparatively small differences in dose or concentration lead to serious therapeutic failure and/or adverse drug reactions which may be persisted, irreversible, slowly reversible, or life-threatening events. Proc. Our findings demonstrated that implementation of pharmaceutical warfarin therapy management for patients with poor quality of anticoagulation was able to improve TTR values when compared to the TTR of the same patient 1 year before starting the follow-up with the pharmacist.
Therefore, we utilized TTR value of 1 year before the implementation of pharmacists warfarin management as a control TTR, for comparing them with the TTR after the implementation of pharmacists warfarin management. The Lancet Haematology (2015). Genet. The identification of such drugs and the call for stricter regulation has made the issue a touchstone for the clinician, patient and regulator. Wilcoxon signed-rank test was performed. warfarin pharmacogenomic algorithm optimization However, it should be noted that the definition does emphasize the importance of dosage titration and patient monitoring. (2018). In addition, the determination of MTC and MEC is not a routine goal of drug development. Mayo Clin. prothrombin time) of warfarin plays an important role in titration and dose selection whereas measurement of its plasma concentrations has little utility in optimizing therapy. (2012). (2005). J. Biomed. These drugs, by their very nature, are dosed at levels where the distance between therapeutic and toxic concentrations is in most instances either extremely narrow or overlapping. Digoxin is a third-line therapy. Data are expressed as mean SE. For more details, the readers should also consult the FDA, Center for Drug Evaluation and Research-CDER (Center for Drug Evaluation and Research | CDER | FDA) and the Office of Generic Drugs (Generic Drugs | FDA). The definition itself is flexible in that it uses both animal and human data to establish a therapeutic ratio, but these very elements are also the definition's weak points. In response to various elements contained in this debate, the Food and Drug Administration (FDA) has had cause to evaluate its current practices and to propose, where appropriate, modification to its various guidelines and guidances. Thus, the possible reasons for the significant TTR improvement observed in our study may be due to the good interaction between the patients and the pharmacist, the adhesion of the patient to the treatment that was checked during the entire follow-up and the pharmacist-driven educational support about the disease and treatment that was given to the patients. The authors declare that they have received grants for the support of this study from So Paulo Research Foundation (FAPESP), grant numbers: #2013/09295-3 and #2016/23454-5. In an effort to evaluate the widespread nature and use of these terms, a search of various biomedical databases was conducted. doi: 10.18632/oncotarget.10944, Motycka, C., Kesgen, C., Smith, S. M., Alvarez, E., and Jones, K. (2011). Then, the clinical pharmacist dispensed the medication (warfarin) to the patient, provided instructions about how to correctly administer it, evaluated possible drug interactions, evaluated possible drugfood interactions, performed dose adjustment, according to guidelines and requested a new INR measurement in 7 days. [28] Thus, there is no need to apply stricter criteria for Narrow Therapeutic Index drugs. Monitoring of PD response (e.g. This medication has a narrow therapeutic range and, consequently, patients usually have difficulty in achieving and maintaining stable target therapeutics. The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. The major differences of our study with previous that have already shown a significant improvement in coagulation therapy are: our study is composed of two phases (retrospective and prospective phases), rather than only retrospective analysis; these previous studies included general patients, whereas our study included only patients with unstable dose and poor quality of warfarin therapy (TTR < 50%); and they are randomized trials, whereas our study was performed by using paired comparisons (the subjects TTR were assessed and compared before and after pharmacist-driven warfarin therapy management, in a way that before receiving pharmacist-guidance the patients received warfarin traditional treatment by physicians) (Saokaew et al., 2012; Verret et al., 2012; Katada et al., 2017). TTR values of this patient group 1 year before the follow-up with the clinical pharmacist indicated poor quality of treatment. Patients were excluded if they presented liver and/or kidney dysfunctions, alcoholism, use of another anticoagulant, and/or chemotherapy treatment.
Effect of standardized warfarin treatment protocol on anticoagulant effect: comparison of a warfarin medication therapy adherence clinic with usual medical care. 16, 670679. Oral anticoagulation in very elderly patients with atrial fibrillation: a nationwide cohort study. Our study has some limitations. J. Haematol. J. Clin. There are some drugs with a single indication, but with multiple toxicity as shown in Figure 2. The term narrow therapeutic index and its abbreviated term Narrow Therapeutic Index are most widely used in this area, but they themselves are subject to interpretation. Protocols study design. (2012). therapeutic window lash pharm toxicology quizlet vs drug Then, the pharmacist re-checked if he/she met the inclusion criteria and explained the study to the patient. Conversely, if the intersubject variability of a PK measure is high and a PKPD relationship exists, PK monitoring is often used for dose optimization. Circ. Effectiveness of pharmacist-participated warfarin therapy management: a systematic review and meta-analysis. If the INR was stable, the patient returned in 30 days. From the literature review, it can be stated that virtually all Narrow Therapeutic Index drugs have low intrasubject variability in PK and PD measures. Ideally, this would allow for the identification of Narrow Therapeutic Index drugs during the drug development process. The FDA has refrained from publishing a list of Narrow Therapeutic Index drugs for a variety of reasons, including but not limited to the fact that all such lists have some degree of bias in them and the fact that Narrow Therapeutic Index drugs defy grouping by simple criteria. In a review published in JAMA in 1999 of the 127 bioequivalence studies submitted to the Office of Generic Drugs in 1997, the mean difference in bioequivalence parameters between the approved generic and reference listed drug was less than 4.3%. Impact of a pharmacist-driven warfarin management protocol on achieving therapeutic International Normalized Ratios. Comparison between the basal and the TTRs calculated in different times (TTR 4 weeks: based on INR tests from visits 0 to 4; TTR 412 weeks: based on INR tests from visits 412; TTR 12 weeks: based on INR tests from visits 012). Intern. Assessment of oral anticoagulation control at two pharmacist-managed clinics in Brazil. Furthermore, in the presence of AF, the incidence rate of VTE is 6.3 per 1,000 persons-year. [128] Coumadin (warfarin) first came into commercial use in 1948 as rat poison. Because of this general acceptance of the two terms, it is apparent that their domination over other alternatives makes either of them an acceptable choice based on usage alone. This record provided information on current warfarin dose (mg/week), daily dose, and INR values. Oral anticoagulant therapy: antithrombotic therapy and prevention of thrombosis, 9th ed: american college of chest physicians evidence-based clinical practice guidelines. A good example of trade-off between risk and efficacy is aspirin. 1), S69S73. Palylyk-Colwell E, Jamali F, Dryden W et al. Earlier, the Canadian Society for Pharmaceutical Sciences Discussion Group proposed the use of the 95% CI limits instead of 90% for both Cmax and AUC.[18]. The LD50 test is not routinely conducted today because of animal rights concerns. By contrast, without AF the incidence rate of VTE is 2.4 per 1,000 persons-year (Lutsey et al., 2018). This definition is as follows: Evidence that the drug products exhibit a narrow therapeutic ratio, e.g., there is less than a 2-fold difference in the median lethal dose (LD50) and the median effective dose (ED50) values, or have a less than 2-fold difference in the minimum toxic concentrations (MTC) and the minimum effective concentrations (MEC) in the blood and safe and effective use of the drug products requires careful dosage titration and patient monitoring. Therefore, the aim of the study was to evaluate a pharmacists warfarin management in patients with poor quality of anticoagulation therapy.
US Office of the Surgeon General, and US National Heart, Lung, and Blood Institute (2008). ), e185Se194S. By basing these criteria on those factors that affect the degree of separation of the concentrations that elicit the therapeutic and the adverse effects, it was attempted to avoid the vagaries inherent in preparing a list of individual drugs themselves. In this situation, aspirin exhibits the characteristics of a Narrow Therapeutic Index drug. doi: 10.1007/s11096-017-0511-x, Downing, A., Mortimer, M., and Hiers, J. Pharmacogenomics 19, 667685 doi: 10.2217/pgs-2017-0207. A propensity score matched comparison of clinical outcomes in atrial fibrillation patients taking vitamin K antagonists: comparing the real-world vs clinical trials. 163, 5459. J. Thromb. The aim of this study was to prospectively evaluate a pharmacists warfarin management in patients with poor quality of anticoagulation therapy (Time in the Therapeutic Range- TTR < 50%). During this study period, for every appointment with a cardiologist, the patients also received pharmacists intervention through one-on-one visit. Genotype-guided warfarin therapy: current status. At the present time, there is no clear consensus on the terminology, definition or characteristics of what constitutes a Narrow Therapeutic Index drug. The level of significance was set at p 0.05. Prevalence, age distribution, and gender of patients with atrial fibrillation. The mean age was 66.6 0.7 years; 47.6% were female. Phys. 
We included patients with AF, over 18 years, and with TTR < 50%, based on the last three values of INR. Additionally, a meta-analysis showed that a 7% improvement in TTR would lead to a reduction of 1 major bleeding event per 100 patient-years, and a 12% improvement in TTR would lead to a reduction of 1 thromboembolic event per 100 patient-years (Wan et al., 2008). These questions are especially relevant in the clinical use of Narrow Therapeutic Index drugs. Front. Furthermore, if the patient administered amiodarone, a dosage change within 1 week of entering the study was considered an exclusion criterion. Results showed that AF patients had an increased risk of ischemic stroke compared to non-AF patients (event number/patient number; incidence = 742/11,064; 5.75%/year vs. 1,399/14,658; 3.00%/year; hazard ratio [HR] 1.93, 95% confidence interval [CI] 1.742.14) (Chao et al., 2018). FIGURE 1. In theory, it is a simple concept that there exists in medicine for which both dose titration and routine clinical monitoring are essential for effective therapy because the dose associated with toxicity is not much greater than the dose required for efficacy. Email: Search for other works by this author on: Narrow Therapeutic Index (NTI) Drugs. It should be noted that the regulatory Agency in Japan is in agreement with the FDA in terms of the CI limits of 80125% for all drugs, including Narrow Therapeutic Index drugs. These drugs are definitely considered as Narrow Therapeutic Index drugs. Conversely, the terms range or window can have a magnitude modifier such as width associated with them. At the retrospective phase, patients receiving warfarin therapy were routinely treated and managed by physicians. The results of this literature survey are summarized in Supplementary Table 1. FIGURE 2. CYP2C9 and VKORC1 polymorphisms are differently distributed in the Brazilian population according to self-declared ethnicity or genetic ancestry. Only through better dose ranging and more flexible dosing strategies in clinical trials can we hope to map out these relationships sufficiently such that we can truly provide the clinician in the label the lowest efficacious dose that maximizes efficacy and minimizes toxicity. LS, MF, NO, and FD recruited the patients, collected data, and critically revised the manuscript. Ann. Recent studies have shown that the pharmacist-driven management of warfarin therapy is beneficial, in agreement with the key finding of this study. The scientific community has been clearly divided. Based on these observations, it is readily seen that the utility of PK or PD monitoring for a Narrow Therapeutic Index drug is associated with both intra- and intersubject variability. [23, 24] In approving all generic drugs, the FDA requires rigorous tests and procedures to assure that the generic drug is interchangeable with the reference drug product under all conditions of use. At the visit 1, 2, 3, and 4, which occurred each 7 days, a new INR test was made and warfarin dosage was adjusted, if it was necessary. From a strictly linguistic point of view, the proper terminology should be either narrow therapeutic window or range. [4345] Clearly, most clinicians do not consider aspirin a Narrow Therapeutic Index drug.
Pharm. 2:e393. (2017). TABLE 1. However, if INR was out the therapeutic target, the patient was asked to return in 7 days. Office of Clinical Pharmacology (OCP), Office of Translational Sciences (OTS), Center for Drug Evaluation and Research (CDER), Food and Drug Administration (FDA). In addition, an interesting meta-analysis suggests that for capturing all effects of pharmacist-driven management, a follow-up time of 6 months is necessary (Saokaew et al., 2010). NTI drugs are those with the potential to cause dose-limiting adverse effects at or near doses required to achieve the desired therapeutic effect and which, in clinical practice, routinely require careful incremental dose titration and quantitative monitoring of drug concentrations or pharmacodynamic effects.
It is not intended to describe a magnitude, such as narrow or wide. The Surgeon Generals Call to Action to Prevent Deep Vein Thrombosis and Pulmonary Embolism. In addition, we compared the antepenultimate, penultimate and last INR before the prospective phase of the study, as well as the INR at 4 and 12 weeks after protocol start. For full access to this pdf, sign in to an existing account, or purchase an annual subscription. Pharmacol. Pharm. Therefore, our findings could not be similar for new-diagnosed and general patients. In 2010, it was estimated that there are 33.5 million people in the world with AF (Feinberg et al., 1995; Chugh et al., 2014; Shantsila and Lip, 2016). First, the ideal design of an interventional study is the randomized control trial. In addition, patients older than 80 years have 515% increased prevalence of AF (Camm et al., 2010). One objective of drug regulation is to obtain a favourable risk/benefit ratio based on the condition being treated and the duration of treatment. To summarize, it is this concept of a concentrationresponse curve and its delineation during drug development that we believe is at the heart of the Narrow Therapeutic Index issue. Benefit of oral anticoagulant over antiplatelet therapy in atrial fibrillation depends on the quality of international normalized ratio control achieved by centers and countries as measured by time in therapeutic range. Res.
Cardiovasc. The results of this investigation, summarized in Supplementary Table 1, indicate that both Narrow Therapeutic Index and Narrow Therapeutic Range, and their variants, are used to almost the same extent in the literature. J. Clin. However, in 1954 it was approved for medical use in the USA. a retrospective study of 2300 consecutive patients with venous thromboembolism. Also, the FDA published a list of NTI in November 1995 in the Guidance for Industry for Immediate Release Solid Oral Dosage From and better known as SUPAC-IR (Supplementary Appendix 1; https://www.fda.gov/regulatory-information/search-fda-guidance-documents/supac-ir-immediate-release-solid-oral-dosage-forms-scale-and-post-approval-changes-chemistry). Haemost. doi: 10.1007/s11096-016-0403-5, Wan, Y., Heneghan, C., Perera, R., Roberts, N., Hollowell, J., Glasziou, P., et al. This definition is more practical as it does not rely upon LD50 values and is based on the clinical experience with the drug. (2008). It may even increase the risk of death. This paper was part of the team at the Food and Drug Administration (FDA) that was formed in 1997 as at the time of Generic drug application for warfarin. Ann. However, at the recent Canadian Expert Advisory Committee on Bioavailability and Bioequivalence meeting held in March 2001,[29] the Narrow Therapeutic Index drugs, referred to as critical drugs were defined as: Comparatively small differences in dose or concentration lead to serious therapeutic failure and/or adverse drug reactions which may be persisted, irreversible, slowly reversible, or life-threatening events. Proc. Our findings demonstrated that implementation of pharmaceutical warfarin therapy management for patients with poor quality of anticoagulation was able to improve TTR values when compared to the TTR of the same patient 1 year before starting the follow-up with the pharmacist.
Therefore, we utilized TTR value of 1 year before the implementation of pharmacists warfarin management as a control TTR, for comparing them with the TTR after the implementation of pharmacists warfarin management. The Lancet Haematology (2015). Genet. The identification of such drugs and the call for stricter regulation has made the issue a touchstone for the clinician, patient and regulator. Wilcoxon signed-rank test was performed. warfarin pharmacogenomic algorithm optimization However, it should be noted that the definition does emphasize the importance of dosage titration and patient monitoring. (2018). In addition, the determination of MTC and MEC is not a routine goal of drug development. Mayo Clin. prothrombin time) of warfarin plays an important role in titration and dose selection whereas measurement of its plasma concentrations has little utility in optimizing therapy. (2012). (2005). J. Biomed. These drugs, by their very nature, are dosed at levels where the distance between therapeutic and toxic concentrations is in most instances either extremely narrow or overlapping. Digoxin is a third-line therapy. Data are expressed as mean SE. For more details, the readers should also consult the FDA, Center for Drug Evaluation and Research-CDER (Center for Drug Evaluation and Research | CDER | FDA) and the Office of Generic Drugs (Generic Drugs | FDA). The definition itself is flexible in that it uses both animal and human data to establish a therapeutic ratio, but these very elements are also the definition's weak points. In response to various elements contained in this debate, the Food and Drug Administration (FDA) has had cause to evaluate its current practices and to propose, where appropriate, modification to its various guidelines and guidances. Thus, the possible reasons for the significant TTR improvement observed in our study may be due to the good interaction between the patients and the pharmacist, the adhesion of the patient to the treatment that was checked during the entire follow-up and the pharmacist-driven educational support about the disease and treatment that was given to the patients. The authors declare that they have received grants for the support of this study from So Paulo Research Foundation (FAPESP), grant numbers: #2013/09295-3 and #2016/23454-5. In an effort to evaluate the widespread nature and use of these terms, a search of various biomedical databases was conducted. doi: 10.18632/oncotarget.10944, Motycka, C., Kesgen, C., Smith, S. M., Alvarez, E., and Jones, K. (2011). Then, the clinical pharmacist dispensed the medication (warfarin) to the patient, provided instructions about how to correctly administer it, evaluated possible drug interactions, evaluated possible drugfood interactions, performed dose adjustment, according to guidelines and requested a new INR measurement in 7 days. [28] Thus, there is no need to apply stricter criteria for Narrow Therapeutic Index drugs. Monitoring of PD response (e.g. This medication has a narrow therapeutic range and, consequently, patients usually have difficulty in achieving and maintaining stable target therapeutics. The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. The major differences of our study with previous that have already shown a significant improvement in coagulation therapy are: our study is composed of two phases (retrospective and prospective phases), rather than only retrospective analysis; these previous studies included general patients, whereas our study included only patients with unstable dose and poor quality of warfarin therapy (TTR < 50%); and they are randomized trials, whereas our study was performed by using paired comparisons (the subjects TTR were assessed and compared before and after pharmacist-driven warfarin therapy management, in a way that before receiving pharmacist-guidance the patients received warfarin traditional treatment by physicians) (Saokaew et al., 2012; Verret et al., 2012; Katada et al., 2017). TTR values of this patient group 1 year before the follow-up with the clinical pharmacist indicated poor quality of treatment. Patients were excluded if they presented liver and/or kidney dysfunctions, alcoholism, use of another anticoagulant, and/or chemotherapy treatment.
Effect of standardized warfarin treatment protocol on anticoagulant effect: comparison of a warfarin medication therapy adherence clinic with usual medical care. 16, 670679. Oral anticoagulation in very elderly patients with atrial fibrillation: a nationwide cohort study. Our study has some limitations. J. Haematol. J. Clin. There are some drugs with a single indication, but with multiple toxicity as shown in Figure 2. The term narrow therapeutic index and its abbreviated term Narrow Therapeutic Index are most widely used in this area, but they themselves are subject to interpretation. Protocols study design. (2012). therapeutic window lash pharm toxicology quizlet vs drug Then, the pharmacist re-checked if he/she met the inclusion criteria and explained the study to the patient. Conversely, if the intersubject variability of a PK measure is high and a PKPD relationship exists, PK monitoring is often used for dose optimization. Circ. Effectiveness of pharmacist-participated warfarin therapy management: a systematic review and meta-analysis. If the INR was stable, the patient returned in 30 days. From the literature review, it can be stated that virtually all Narrow Therapeutic Index drugs have low intrasubject variability in PK and PD measures. Ideally, this would allow for the identification of Narrow Therapeutic Index drugs during the drug development process. The FDA has refrained from publishing a list of Narrow Therapeutic Index drugs for a variety of reasons, including but not limited to the fact that all such lists have some degree of bias in them and the fact that Narrow Therapeutic Index drugs defy grouping by simple criteria. In a review published in JAMA in 1999 of the 127 bioequivalence studies submitted to the Office of Generic Drugs in 1997, the mean difference in bioequivalence parameters between the approved generic and reference listed drug was less than 4.3%. Impact of a pharmacist-driven warfarin management protocol on achieving therapeutic International Normalized Ratios. Comparison between the basal and the TTRs calculated in different times (TTR 4 weeks: based on INR tests from visits 0 to 4; TTR 412 weeks: based on INR tests from visits 412; TTR 12 weeks: based on INR tests from visits 012). Intern. Assessment of oral anticoagulation control at two pharmacist-managed clinics in Brazil. Furthermore, in the presence of AF, the incidence rate of VTE is 6.3 per 1,000 persons-year. [128] Coumadin (warfarin) first came into commercial use in 1948 as rat poison. Because of this general acceptance of the two terms, it is apparent that their domination over other alternatives makes either of them an acceptable choice based on usage alone. This record provided information on current warfarin dose (mg/week), daily dose, and INR values. Oral anticoagulant therapy: antithrombotic therapy and prevention of thrombosis, 9th ed: american college of chest physicians evidence-based clinical practice guidelines. A good example of trade-off between risk and efficacy is aspirin. 1), S69S73. Palylyk-Colwell E, Jamali F, Dryden W et al. Earlier, the Canadian Society for Pharmaceutical Sciences Discussion Group proposed the use of the 95% CI limits instead of 90% for both Cmax and AUC.[18]. The LD50 test is not routinely conducted today because of animal rights concerns. By contrast, without AF the incidence rate of VTE is 2.4 per 1,000 persons-year (Lutsey et al., 2018). This definition is as follows: Evidence that the drug products exhibit a narrow therapeutic ratio, e.g., there is less than a 2-fold difference in the median lethal dose (LD50) and the median effective dose (ED50) values, or have a less than 2-fold difference in the minimum toxic concentrations (MTC) and the minimum effective concentrations (MEC) in the blood and safe and effective use of the drug products requires careful dosage titration and patient monitoring. Therefore, the aim of the study was to evaluate a pharmacists warfarin management in patients with poor quality of anticoagulation therapy.
US Office of the Surgeon General, and US National Heart, Lung, and Blood Institute (2008). ), e185Se194S. By basing these criteria on those factors that affect the degree of separation of the concentrations that elicit the therapeutic and the adverse effects, it was attempted to avoid the vagaries inherent in preparing a list of individual drugs themselves. In this situation, aspirin exhibits the characteristics of a Narrow Therapeutic Index drug. doi: 10.1007/s11096-017-0511-x, Downing, A., Mortimer, M., and Hiers, J. Pharmacogenomics 19, 667685 doi: 10.2217/pgs-2017-0207. A propensity score matched comparison of clinical outcomes in atrial fibrillation patients taking vitamin K antagonists: comparing the real-world vs clinical trials. 163, 5459. J. Thromb. The aim of this study was to prospectively evaluate a pharmacists warfarin management in patients with poor quality of anticoagulation therapy (Time in the Therapeutic Range- TTR < 50%). During this study period, for every appointment with a cardiologist, the patients also received pharmacists intervention through one-on-one visit. Genotype-guided warfarin therapy: current status. At the present time, there is no clear consensus on the terminology, definition or characteristics of what constitutes a Narrow Therapeutic Index drug. The level of significance was set at p 0.05. Prevalence, age distribution, and gender of patients with atrial fibrillation. The mean age was 66.6 0.7 years; 47.6% were female. Phys. We included patients with AF, over 18 years, and with TTR < 50%, based on the last three values of INR. Additionally, a meta-analysis showed that a 7% improvement in TTR would lead to a reduction of 1 major bleeding event per 100 patient-years, and a 12% improvement in TTR would lead to a reduction of 1 thromboembolic event per 100 patient-years (Wan et al., 2008). These questions are especially relevant in the clinical use of Narrow Therapeutic Index drugs. Front. Furthermore, if the patient administered amiodarone, a dosage change within 1 week of entering the study was considered an exclusion criterion. Results showed that AF patients had an increased risk of ischemic stroke compared to non-AF patients (event number/patient number; incidence = 742/11,064; 5.75%/year vs. 1,399/14,658; 3.00%/year; hazard ratio [HR] 1.93, 95% confidence interval [CI] 1.742.14) (Chao et al., 2018). FIGURE 1. In theory, it is a simple concept that there exists in medicine for which both dose titration and routine clinical monitoring are essential for effective therapy because the dose associated with toxicity is not much greater than the dose required for efficacy. Email: Search for other works by this author on: Narrow Therapeutic Index (NTI) Drugs. It should be noted that the regulatory Agency in Japan is in agreement with the FDA in terms of the CI limits of 80125% for all drugs, including Narrow Therapeutic Index drugs. These drugs are definitely considered as Narrow Therapeutic Index drugs. Conversely, the terms range or window can have a magnitude modifier such as width associated with them. At the retrospective phase, patients receiving warfarin therapy were routinely treated and managed by physicians. The results of this literature survey are summarized in Supplementary Table 1. FIGURE 2. CYP2C9 and VKORC1 polymorphisms are differently distributed in the Brazilian population according to self-declared ethnicity or genetic ancestry. Only through better dose ranging and more flexible dosing strategies in clinical trials can we hope to map out these relationships sufficiently such that we can truly provide the clinician in the label the lowest efficacious dose that maximizes efficacy and minimizes toxicity. LS, MF, NO, and FD recruited the patients, collected data, and critically revised the manuscript. Ann. Recent studies have shown that the pharmacist-driven management of warfarin therapy is beneficial, in agreement with the key finding of this study. The scientific community has been clearly divided. Based on these observations, it is readily seen that the utility of PK or PD monitoring for a Narrow Therapeutic Index drug is associated with both intra- and intersubject variability. [23, 24] In approving all generic drugs, the FDA requires rigorous tests and procedures to assure that the generic drug is interchangeable with the reference drug product under all conditions of use. At the visit 1, 2, 3, and 4, which occurred each 7 days, a new INR test was made and warfarin dosage was adjusted, if it was necessary. From a strictly linguistic point of view, the proper terminology should be either narrow therapeutic window or range. [4345] Clearly, most clinicians do not consider aspirin a Narrow Therapeutic Index drug. Pharm. 2:e393. (2017). TABLE 1. However, if INR was out the therapeutic target, the patient was asked to return in 7 days. Office of Clinical Pharmacology (OCP), Office of Translational Sciences (OTS), Center for Drug Evaluation and Research (CDER), Food and Drug Administration (FDA). In addition, an interesting meta-analysis suggests that for capturing all effects of pharmacist-driven management, a follow-up time of 6 months is necessary (Saokaew et al., 2010). NTI drugs are those with the potential to cause dose-limiting adverse effects at or near doses required to achieve the desired therapeutic effect and which, in clinical practice, routinely require careful incremental dose titration and quantitative monitoring of drug concentrations or pharmacodynamic effects.