Discovery and optimization of a highly efficacious class of 5-aryl-2-aminopyridines as FMS-like tyrosine kinase 3 (FLT3) inhibitors.

Based on a putative binding mode of quizartinib (AC220, 1), a potent FMS-like tyrosine kinase 3 (FLT3) inhibitor in Phase III clinical development, we have designed de novo a simpler aminopyridine-based hinge binding motif. Further optimization focusing on maximizing in vivo efficacy and minimizing CYP3A4 time-dependent inhibition resulted in a highly efficacious compound (6s) in tumor xenograft model for further preclinical development.

The effects of copayments on medication adherence during the first two years of prescription drug treatment.

OBJECTIVE: The aim of this study was to examine effects of initial prescription copayment size and observed increase on adherence by analyzing data from a managed care database. METHODS: Medical-pharmacy claims data were abstracted from the Integrated Health Care Information Services (IHCIS) National Managed Care Benchmark database for primary employer-sponsored subscribers. Incident fills and refills for the 10 most common medication groups between 2001 and 2003 were predicted by size and observed increase in copayment with the use of survival analysis. RESULTS: High copayments and observed copayment increases were associated with termination of medication use. Whereas effects of copayment level were limited to the first few fills, effects of observed increases in copayments were persistent. CONCLUSIONS: The strategy of increasing initially low copayments after the patient has made enough fills to become insensitive to copayment level is contraindicated by observed increases in copayment, predicting termination. However, other financial incentives might nonetheless help reduce early termination of medication use.

Antidepressant adherence and medical resource use among managed care patients with anxiety disorders.

OBJECTIVES: This study evaluated adherence with selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs) among patients who newly initiated therapy for anxiety with or without comorbid depression; the study also quantified the health-related economic consequences of nonadherence. METHODS: A large managed care database was used to gather retrospective data for patients with anxiety disorders who had a prescription for an antidepressant between July 1, 2001, and December 31, 2002. The relationship between antidepressant adherence and medical resource utilization was assessed; the analysis controlled for age, gender, utilization of mental health specialty care, change in medication, whether the dosage was titrated, costs in the six months before the prescription for an antidepressant, and comorbid physical conditions. RESULTS: Of the 13,085 patients with anxiety diagnoses who met the criteria for study inclusion, 57 percent were nonadherent to antidepressant therapy at six months. Patients who received mental health specialty care were more likely than those who did not receive such care to be adherent to therapy (48.5 percent compared with 40.7 percent; p<.001). Those with dual diagnoses of anxiety and depression were more likely than those with anxiety alone to be adherent to therapy (46.8 percent compared with 40.2 percent; p<.001). Those with a coded diagnosis of posttraumatic stress disorder had the highest medical costs. Patients with anxiety and depression had significantly higher total costs than patients with anxiety alone. Adherent patients who did not have a change in medication or a titrated dosage had significantly lower medical costs than nonadherent patients; however, total costs (medical plus pharmacy) were similar. CONCLUSIONS: Nonadherence with antidepressant therapy in anxiety disorders is common, but mental health specialty care may be associated with improved adherence. Lower medical costs for adherent patients who did not have a change in medication or a titrated dosage offset the increase in pharmacy costs, resulting in total costs (medical plus pharmacy) that were similar to those of nonadherent patients.

Methods for evaluating patient adherence to antidepressant therapy: a real-world comparison of adherence and economic outcomes.

OBJECTIVE: The objective of this study was to differentiate between 3 measures of antidepressant adherence with regard to the number of patients deemed adherent to therapy and the association between adherence and resource utilization. DESIGN AND SETTING: The authors conducted a retrospective study of patients initiating selective serotonin reuptake inhibitor (SSRI) therapy for depression and/or anxiety between July 2001 and June 2002 in a large national managed care database. MAIN OUTCOME MEASURES: Rates of 6-month SSRI adherence were measured by 3 different metrics: length of therapy (LOT), medication possession ratio (MPR), and combined MPR/LOT. Differences in resource utilization for each adherence metric were measured for patients deemed as 1) adherent, 2) nonadherent, 3) therapy changers, and 4) dose titraters. RESULTS: There were 22,947 patients meeting study criteria. Although statistically different, 6-month adherence rates were numerically similar across all methods (LOT, 44.6%; MPR, 43.3%; and MPR/LOT, 42.9%, P < 0.001); approximately 57% of patients were nonadherent to therapy. Regardless of metric, the adherent cohort incurred the lowest yearly medical costs, followed by the nonadherent, titrate, and therapy change cohorts (P < 0.001 between adherent cohort and all other cohorts). The LOT method produced the greatest difference in yearly medical costs between adherent and nonadherent patients (Dollars 511) followed by MPR/LOT (Dollars 432) and MPR (Dollars 423). When antidepressant prescription costs were added to medical costs, patients requiring a therapy change and titrating therapy incurred higher costs than adherent patients, whereas nonadherent and adherent patients incurred similar costs. CONCLUSION: Regardless of adherence metric, approximately 43% of patients were adherent to antidepressant therapy, and adherent patients were associated with the lowest yearly medical costs.

Impact of antidepressant drug adherence on comorbid medication use and resource utilization.

BACKGROUND: Patients with depression are often nonadherent to therapy for depression and chronic comorbid conditions. METHODS: To determine whether improved antidepressant medication adherence is associated with an increased likelihood of chronic comorbid disease medication adherence and reduced medical costs, we conducted a retrospective study of patients initiating antidepressant drug therapy with evidence of dyslipidemia, coronary artery disease (CAD), or both; diabetes mellitus (DM); or CAD/dyslipidemia and DM identified from a claims database. Measures included antidepressant medication adherence, measured by medication possession ratio during 180 days without a 15-day gap before 90 days of therapy; comorbid medication adherence, measured by medication possession ratio during 1 year; and the association between improved antidepressant drug adherence and disease-specific and total medical costs. RESULTS: Of 8040 patients meeting the study criteria, those adherent to antidepressant medication were more likely to be adherent to comorbid therapy vs those nonadherent to antidepressant drug therapy (CAD/dyslipidemia: odds ratio [OR], 2.13; DM: OR, 1.82; and CAD/dyslipidemia/DM: OR, 1.45; P<.001 for all). Patients adherent to antidepressant drug therapy also had significantly lower disease-specific charges vs nonadherent patients (17% lower in CAD/dyslipidemia, P = .02; 8% lower in DM, P = .39; and 14% lower in CAD/dyslipidemia/DM, P = .38). These patients also incurred lower total medical charges (6.4% lower in CAD/dyslipidemia, P = .048; 11.8% lower in DM, P = .04; and 19.8% lower in CAD/dyslipidemia/DM, P = .03). CONCLUSIONS: Antidepressant drug adherence was associated with increased comorbid disease medication adherence and reduced total medical costs for CAD/dyslipidemia, DM, and CAD/dyslipidemia/DM. Future studies should investigate the relationship between increased adherence and costs beyond 1 year.