Current methods of improving medication adherence for chronic health problems are mostly complex, labor-intensive, and not predictably effective. The full benefits of medications cannot be realized at currently achievable levels of adherence; therefore, more studies of innovative approaches to assist patients to follow prescriptions for medications are needed.

Low adherence to prescribed medical regimens is a ubiquitous problem. Typical adherence rates are about 50% for medications and are much lower for lifestyle prescriptions and other more behaviorally demanding regimens. In addition, many patients with medical problems do not seek care or drop out of care prematurely. Although accurate measures of low adherence are lacking for many regimens, simple measures, such as directly asking patients and watching for appointment nonattendance and treatment nonresponse, will detect most problems. For short-term regimens (< or =2 weeks), adherence to medications is readily achieved by giving clear instructions. On the other hand, improving adherence to long-term regimens requires combinations of information about the regimen, counseling about the importance of adherence and how to organize medication taking, reminders about appointments and adherence, rewards and recognition for the patient's efforts to follow the regimen, and enlisting social support from family and friends. Successful interventions for long-term regimens are all labor-intensive but ultimately can be cost-effective.

Although it is known that FcRn, the neonatal Fc-receptor, functions to protect immune gamma globulin (IgG) from elimination, the influence of FcRn on the tissue distribution of IgG has not been quantified. In the present work, a physiologically-based pharmacokinetic (PBPK) model has been developed to characterize and predict IgG disposition in plasma and in tissues. The model includes nine major compartments, connected in an anatomical manner, to represent tissues known to play a significant role in IgG disposition. Each tissue compartment was subdivided into vascular, endosomal and interstitial spaces. IgG transport between the blood and interstitial compartments may proceed by convection through paracellular pores in the vascular endothelium, or via FcRn-mediated transcytosis across vascular endosomal cells. The model was utilized to characterize plasma concentration-time data for 7E3, a monoclonal antiplatelet IgG1 antibody, in control and FcRn-knockout (KO) mice. These data showed that high dose intravenous immunoglobulin (IVIG), 1g/kg, increased 7E3 clearance in control mice from 5.2 +/- 0.3 to 14.4 +/- 1.4 ml/d/kg; however, IVIG failed to increase the clearance of 7E3 in KO mice (72.5 +/- 4.0 vs. 61.0 +/- 3.6 ml/d/kg). Based on model fitting to the 7E3 plasma concentration data, simulations were conducted to predict tissue concentrations of IgG in control and in KO mice, and the predictions were then tested by assessing 7E3 tissue distribution in KO mice and control mice. 7E3 was radiolabeled with Iodine-125 using chloramine T method, and (125)I-7E3 IgG was administered at a dose of 8 mg/kg to control and KO mice. At various time points, sub-groups of 3 mice were sacrificed, blood and tissue samples were collected, and radioactivity assessed by gamma counting. PBPK model performance was assessed by comparing model predictions with the observed data. The model accurately predicted 7E3 tissue concentrations, with mean predicted vs. observed AUC ratios of 1.04 +/- 0.2 and 0.86 +/- 0.3 in control and FcRn-KO mice. The PBPK model, which incorporates the influence of FcRn on IgG clearance and disposition, was found to provide accurate predictions of IgG tissue kinetics in control and FcRn-knockout mice.

Purpose To compare standard-of-care (SoC) trastuzumab plus chemotherapy with higher-dose (HD) trastuzumab plus chemotherapy to investigate whether HD trastuzumab increases trastuzumab serum trough concentration (C) levels and increases overall survival (OS) in first-line human epidermal growth factor receptor 2-positive metastatic gastric or gastroesophageal junction adenocarcinoma. Patients and Methods Patients with Eastern Cooperative Oncology Group performance status 2, no prior gastrectomy, and ≥ two metastatic sites were randomly assigned at a one-to-one ratio to loading-dose trastuzumab 8 mg/kg followed by SoC trastuzumab maintenance 6 mg/kg every 3 weeks or loading-dose trastuzumab 8 mg/kg followed by HD trastuzumab maintenance 10 mg/kg every 3 weeks until progression; treatment in each arm was combined with cisplatin 80 mg/m plus capecitabine 800 mg/m twice per day in cycles 1 to 6. The primary objective was HD trastuzumab OS superiority (all randomly assigned patients [full-analysis set]). Final results are from an interim analysis for futility (boundary hazard ratio [HR] ≥ 0.95) at 125 deaths. Results At clinical cutoff, 248 patients had been randomly assigned. A marked increase in mean trastuzumab C was observed after the first HD trastuzumab cycle versus SoC trastuzumab. In the full-analysis set, median OS was 12.5 months in the SoC trastuzumab arm and 10.6 months in the HD trastuzumab arm (stratified HR, 1.24; 95% CI, 0.86 to 1.78; P = .2401). Results were similar in the per-protocol set (cycle 1 trastuzumab C < 12 µg/mL). Safety was comparable between arms. Conclusion HD trastuzumab maintenance dosing was associated with higher trastuzumab concentrations, no increased efficacy, and no new safety signals. HELOISE confirms standard-dose trastuzumab (loading dose of 8 mg/kg followed by 6 mg/kg maintenance dose every 3 weeks) with chemotherapy as the SoC for first-line treatment of human epidermal growth factor receptor 2-positive metastatic gastric or gastroesophageal junction adenocarcinoma.

Abstract. It has been suggested that the neonatal Fc receptor (FcRn) is a primary determinant of the distribution of IgG to the brain. In the present report, 125 I-labeled 7E3, a monoclonal IgG1 antibody, was injected intravenously to groups of FcRn-deficient mice and C57BL/6J control mice. Sub-groups of three mice were sacrificed at several time points. Blood and brain tissue were harvested and radioactivity was assessed. Antibody concentrations in brain were corrected for residual blood using 51 Cr-labeled red blood cells. Data were analyzed via WinNonlin, and areas under plasma and tissue concentration vs. time curves (AUCs) were assessed via the Bailer method. The apparent plasma elimination half-life and clearance of 7E3 were 13.61±0.61 days and 6.5±0.10 ml/day/kg in control mice and 0.70±0.05 days and 63.5±2.7 ml/day/kg in the knockout mice. Plasma and brain AUCs (0-10 days) were found to be 3,338.7± 50.4 and 7.46±0.5 nM day in control animals and 781.2±16.6 and 1.65±0.1 nM day in FcRn-deficient animals. There was no significant difference between brain-to-plasma AUC ratios in control and FcRndeficient mice (0.0022±0.00015 vs. 0.0021±0.00011, p=0.3347). Two-way analysis of variance showed no significant differences, at any time point, between brain-to-plasma concentration ratios determined from control and knockout animals. The results suggest that FcRn does not contribute significantly to the "blood-brain barrier" for IgG in mice, and the data suggest that FcRn is not responsible for the low exposure of IgG in the brain relative to plasma.