These authors contributed equally to this work as first authors. McInnes GT. Between 25% and 50% of patients prescribed divalproex, carbamazepine, phenobarbital, phenytoin, or tacrolimus did not have a serum concentration evaluated within the 1-year period. OBJECTIVE: To evaluate whether lamotrigine should be classified as a narrow therapeutic index (NTI) drug. Analyses were performed using SAS version 8.2 or 9.1 (SAS Institute Inc, Cary, NC). ScienceDirect is a registered trademark of Elsevier B.V. ScienceDirect is a registered trademark of Elsevier B.V. 9. Because the 10th site did not contribute data for 4 NTR drugs, the percentage of patients without monitoring for all NTR study drugs could not be determined. Patients prescribed digoxin (77 vs 74 years, P < .001), procainamide (75 vs 71 years, P = .02), or theophylline (65 vs 61 years, P < .001) who were less likely to be monitored were younger, while patients prescribed carbamazepine (45 vs 49 years, P < .001), divalproex (44 vs 47 years, P < .001), or primidone (55 vs 69 years, P < .001) who were less likely to be monitored were older. Your co-authors must send a completed Publishing Agreement Form to Neurology Staff (not necessary for the lead/corresponding author as the form below will suffice) before you upload your comment. 11. We thank Parker Pettus, MS, for leading the data management and computer programming required for this study. and apply to letter. (P4.267). Yet, we found that the presence of either diagnosis was similarly protective against lack of monitoring (Table 2). 6. Your role and/or occupation, e.g. 1988;296:1110-1113. Identification of the key target profiles underlying the drugs of narrow therapeutic index for treating cancer and cardiovascular disease. For example, drug concentration monitoring is recommended as a quality-of-care indicator for patients taking phenytoin, phenobarbital, divalproex sodium, and carbamazepine.5,6 Concentration monitoring of many NTR drugs is routinely available at healthcare laboratories, but little is known about the frequency of monitoring among ambulatory patients. Therapeutic drug monitoring is useful for drugs that lack correlation between dose and pharmacodynamic properties, for drugs that have nonlinear correlations between dose and effect, and for drugs that have a narrow therapeutic range (NTR) between the dose necessary to achieve beneficial effects and the dose that causes serious adverse effects when there is a direct concentration-effect relationship. 4th ed. (Exception: original author replies can include all original authors of the article).
We acknowledge the programmers from each of the health maintenance organizations. 'MacMoody'. 
These factors were associated with a lower likelihood of lacking monitoring (ie, patients with these factors were more likely to be monitored). Computational and Structural Biotechnology Journal, https://doi.org/10.1016/j.csbj.2021.04.035. 14. Clark DO, Von Korff M, Saunders K, Baluch WM, Simon GE.
For example, a patient dispensed a 30-day supply met the criterion of continued dispensings if no more than 75 days (30 days + [1.5 30 days]) elapsed between the date of one dispensing and the date of the subsequent dispensing. For example, it is feasible that the high monitoring rate observed with cyclosporine is related to the fact that patients prescribed this drug have a high number of outpatient visits (median, 11 visits in a 6-month period) (Table 1). Unfortunately, this study was not designed to evaluate whether a relationship existed between dosage and monitoring, nor was it designed to differentiate between drug concentration monitoring that was not performed because it was not ordered vs because the patient did not obtain the ordered test. A dispensing gap was ignored if it was less than 1.5 times the dispensed days' supply. Younger age was associated with lack of monitoring for patients prescribed digoxin (adjusted odds ratio, 1.86; 95% confidence interval, 1.39-2.48) and theophylline (adjusted odds ratio, 1.58; 95% confidence interval, 1.23-2.04), while older age was associated with lack of monitoring for patients prescribed carbamazepine (adjusted odds ratio, 0.59; 95% confidence interval, 0.44-0.80) and divalproex (adjusted odds ratio, 0.50; 95% confidence interval, 0.38-0.66). Consequently, ten shared features and four unique features were identified for both diseases to distinguish NTI from NNTI drug targets. National Committee for Quality Assurance. NCQA releases HEDIS 2006: new measures address overuse, follow-up [press release]. Ther Drug Monit. This study was supported by cooperative agreement U18 HS 11843 and the HMO Research Network Center for Education and Research in Therapeutics, funded by the Agency for Healthcare Research and Quality, Rockville, Md. The study sample was drawn from a data set of 2 020 037 individuals, consisting of approximately 200 000 randomly selected health plan members from each of the 10 organizations. Vol 2. Almost 18 000 patients (n = 17 748) met the eligibility criteria for the study; these patients represented 18 821 individual patient-drug therapy combinations (5.7% of patients received > 1 study drug). 1989;27:281-284. Copyright 2022 Elsevier B.V. or its licensors or contributors.
1995;274:1622-1626. 'Orthopedic Surgeon'. The results of this study provide information to guide thoughtful establishment of quality-of-care indicators related to NTR drug monitoring in ambulatory patients. This difference was significant for digoxin (10 vs 8 visits, P < .001), theophylline (6 vs 4 visits, P < .001), divalproex (7 vs 5 visits, P < .001), carbamazepine (6 vs 4 visits, P < .001), phenytoin (5 vs 3 visits, P < .001), lithium (8 vs 5 visits, P < .001), and phenobarbital (5 vs 4 visits, P = .01). 
Fewer outpatient visits and a diagnosis of chronic obstructive pulmonary disease were associated with lacking theophylline monitoring. For carbamazepine, the association between being in the oldest age group and having a lower likelihood of monitoring was significant in patients with a mental health diagnosis (odds ratio, 0.24; 95% confidence interval, 0.11-0.54 for the youngest age group). Five years of anticonvulsant monitoring on site at the epilepsy clinic. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM, eds. Bauer LA. Online ISSN:1526-632X, The most widely read and highly cited peer-reviewed neurology journal, Lamotrigine, a Narrow Therapeutic Index Drug or Not? The laboratory test date was the date the test was performed or the result was reported. Dr. Jiang has nothing to disclose. 16. CONCLUSIONS: Data reviewed do not indicate that lamotrigine possesses all the general characteristics of NTI drugs. Am J Hosp Pharm. The HMO Research Network. 
DESIGN/METHODS: We collected literature, new drug application, and abbreviated new drug application (ANDA) data to assess whether lamotrigine possesses the following general characteristics of NTI drugs: a) little separation between therapeutic and toxic doses (or the associated drug concentrations); b) sub-therapeutic concentrations lead to serious therapeutic failure; c) subject to therapeutic drug monitoring (TDM); d) possess low-to-moderate (i.e., 30%) within-subject variability; e) in clinical practice, doses often adjusted in very small increments (<20%). Patient characteristics are given in Table 1. Whether the laboratory test was performed was assessed from the presence of an administrative claim for the test. Because patients prescribed carbamazepine or divalproex who did not have a seizure diagnosis or a mental health diagnosis had characteristics that were different from those of individuals with these diagnoses (Table 3), we analyzed these patient groups separately. Patient outcomes should be used to guide the refinement of existing NTR drug monitoring quality-of-care indicators in ambulatory patients. Study Supported by: FDA. The first study objective was to assess the proportion of ambulatory patients receiving continuous ongoing therapy with an NTR drug who did not have at least 1 drug serum concentration monitored within a 1-year period. Descriptive statistics were computed to characterize patients, drug dispensings, and drug concentration monitoring for each drug cohort. 8. The most consistent patient characteristic associated with lack of monitoring was a low number of outpatient visits, a finding that is intuitive. Dr. Polli has nothing to disclose. Address correspondence to: Marsha A. Raebel, PharmD, Clinical Research Unit, Kaiser Permanente of Colorado, PO Box 378066, Denver, CO 80237-8066. Continued dispensings were present when no interval between prescription refills was greater than the dispensed days' supply plus 1.5 times the dispensed days' supply. We undertook a study to assess drug concentration monitoring in ambulatory patients receiving NTR drugs. The negative predictive value, the percentage of patients who did not have serum drug concentration monitoring according to administrative data that was also not documented in medical records, was good (85% [34/40] for digoxin, 74% [14/19] for carbamazepine, and 79% [11/14] for cyclosporine). Medical record abstraction was considered the gold standard, and abstraction data were compared with administrative data to determine the sensitivity, specificity, positive predictive value, and negative predictive value of administrative information about drug concentration monitoring. Chan KA; HMO Research Network CERTs Patient Safety Study Investigators. Because patient race was correlated with poverty and with education (Spearman rank correlation coefficient [r] range for race and poverty for individual drugs, -0.43 to -0.53; and r range for race and education for individual drugs, 0.36-0.45) and because poverty and education were correlated (r range for poverty and education for individual drugs, -0.31 to -0.63), race and poverty were not considered further in the analysis. Submitted comments are subject to editing and editor review prior to posting. 7. To avoid inadvertent inclusion of new drug users in the study cohort, prevalent ongoing therapy was defined as beginning with the second dispensing of that drug in the data set and continuing from the second dispensing date for 12 months or longer. Residential street address was combined with census-block level data from the 2000 US Census data to construct proxies of patient race, education, and poverty.10. An appropriate therapeutic index is crucial for drug discovery and development since narrow therapeutic index (NTI) drugs with slight dosage variation may induce severe adverse drug reactions or potential treatment failure. Chichester, UK: John Wiley & Sons Inc; 2005:261-269. Logistic regression analysis was used to evaluate associations between patient characteristics and lack of monitoring for the 6 prescribed drugs that accounted for 91% of the study patients (Table 2). To date, the shared characteristics underlying the targets of NTI drugs have been explored by several studies, which have been applied to identify potential drug targets.
Patients prescribed digoxin (n = 7153), divalproex (n = 2209), carbamazepine (n = 1876), phenytoin (n = 2232), theophylline (n = 2195), and lithium (n = 1487) accounted for 91% of the study patients. Kreiger N, Chen JT, Waterman PD, Soobader MJ, Subramanian SV, Carson R. Geocoding and monitoring US socioeconomic inequalities in mortality and cancer incidence: does choice of area-based measure and geographic level matter? 13. Available at: http://www.ncqa.org/communications/news/hedis_2006.htm. Compliance with criteria necessary for effective drug concentration monitoring. The goal of therapeutic drug monitoring is to guide dosing by means of drug concentration measurements. All rights reserved. Conclusions: A substantial proportion of ambulatory patients receiving drugs with narrow intervals between doses resulting in beneficial and adverse effects did not have serum drug concentration monitoring during 1 year of use. A prospective evaluation of therapeutic drug monitoring. However, the generalizability of our results is limited by the fact that quality of care and the accuracy of administrative data vary across organizations. Surprisingly high proportions of patients prescribed digoxin, theophylline, phenytoin, carbamazepine, procainamide, quinidine, primidone, divalproex, and phenobarbital (all medications with an NTR) do not have drug concentrations monitored at least yearly.
Br J Clin Pharmacol. 1993;15:83-90. The median number of drug dispensings during 1 year ranged from 6 for digoxin to 12 for cyclosporine (data not shown). Appropriateness of antiepileptic drug level monitoring. J Manag Care Pharm. Use of serum drug concentrations in outpatient clinics. Clinical implications of this finding need to be evaluated. The same rationale can be applied to patients prescribed divalproex who do not have a seizure diagnosis or a mental health diagnosis. The study sample was limited to prevalent users who had continued drug dispensings of and ongoing therapy with an NTR drug. A consistent association between patients' median age and lack of monitoring was not observed in the univariate analysis. These computational discoveries, as well as the newly found features, suggest that in the clinical study of avoiding narrow therapeutic index in those diseases, the ability of target to be a hub and the efficiency of target signaling in the human PPI network should be considered, and it could thus provide novel guidance in the drug discovery and clinical research process and help to estimate the drug safety of cancer and cardiovascular disease. Monitoring drug concentrations is viewed as a quality measure associated with avoiding preventable drug-related morbidity and disease exacerbations by organizations, including the National Committee for Quality Assurance in its Health Employer Information Data Set.5,6 The findings of our study can be used by organizations to improve rates of drug concentration monitoring through implementing guidelines that target the patient risk groups we identify herein as lacking monitoring. 
