These findings suggest that nonadherence to antiepileptic drugs can have serious or fatal consequences for patients with epilepsy.

. Patients aged ‡18 years with one or more neurologist visit with an epilepsy diagnosis and two or more pharmacy claims for AEDs were included. Medication possession ratio (MPR) was used to evaluate AED adherence with MPR ‡ 0.80 considered adherent and <0.80 considered nonadherent. The association of nonadherence with utilization outcomes [hospitalizations, inpatient days, emergency department (ED), and outpatient visits] was assessed with univariate and multivariate Poisson regressions. Quarterly per-patient inpatient, outpatient, ED, and pharmacy costs were calculated across nonadherent and adherent quarters for the younger than 65 population (under-65) and cost differences were computed. Adjusted incremental costs of nonadherence were estimated with multivariate Tobit regression models. Results: A total of 33,658 patients were included (28,470 under-65), together contributing 388,564 treated quarters (26% nonadherent). In multivariate analyses, AED nonadherence was associated with significantly higher incidence of hospitalizations [incident rate ratio (IRR) = 1.39, 95% confidence interval (CI) = 1.37-1.41], inpatient days (IRR = 1.76, 95% CI = 1.75-1.78), and ED visits (IRR = 1.19, 95% CI = 1.18-1.21). Nonadherence was associated with cost increases related to serious outcomes, including inpatient ($4,320 additional cost per quarter, 95% CI = $4,077-$4,564) and ED services ($303 additional cost per quarter, 95% CI = $273-$334), but lower costs for outpatient and pharmacy services, likely because of nonadherent behavior. Discussion: Nonadherence to AEDs appears to be associated with serious outcomes, as evidenced by increased utilization and costs of inpatient and ED services.

Purpose: Rational development of targeted MET inhibitors for cancer treatment requires a quantitative understanding of target pharmacodynamics, including molecular target engagement, mechanism of action, and duration of effect.Experimental Design: Sandwich immunoassays and specimen handling procedures were developed and validated for quantifying full-length MET and its key phosphospecies (pMET) in core tumor biopsies. MET was captured using an antibody to the extracellular domain and then probed using antibodies to its C-terminus (full-length) and epitopes containing pY1234/ 1235, pY1235, and pY1356. Using pMET:MET ratios as assay endpoints, MET inhibitor pharmacodynamics were characterized in MET-amplified and -compensated (VEGFR blockade) models.Results: By limiting cold ischemia time to less than two minutes, the pharmacodynamic effects of the MET inhibitors PHA665752 and PF02341066 (crizotinib) were quantifiable using core needle biopsies of human gastric carcinoma xenografts (GTL-16 and SNU5). One dose decreased pY1234/1235 MET: MET, pY1235-MET:MET, and pY1356-MET:MET ratios by 60% to 80% within 4 hours, but this effect was not fully sustained despite continued daily dosing. VEGFR blockade by pazopanib increased pY1235-MET:MET and pY1356-MET:MET ratios, which was reversed by tivantinib. Full-length MET was quantifiable in 5 of 5 core needle samples obtained from a resected hereditary papillary renal carcinoma, but the levels of pMET species were near the assay lower limit of quantitation.Conclusions: These validated immunoassays for pharmacodynamic biomarkers of MET signaling are suitable for studying MET responses in amplified cancers as well as compensatory responses to VEGFR blockade. Incorporating pharmacodynamic biomarker studies into clinical trials of MET inhibitors could provide critical proof of mechanism and proof of concept for the field.

Evidence suggests that inhaled tobramycin, a key chronic suppressive therapy, can reduce other healthcare costs. The main determinants of the cost of care include disease severity and respiratory infection. Costs vary widely by country. There is evidence that inhaled tobramycin and oral azithromycin improve quality of life and that treatment setting and patient convenience may also impact on quality of life. Antibiotic treatment compliance varied significantly and depended on the method of measurement, with more subjective measures tending to be higher. This review concludes by offering directions for future research.