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The effect of subcutaneous (SC) peginterferon β-1a exposure on reduction of gadolinium-enhanced (Gd+) lesion count over time was evaluated in patients with relapsing-remitting multiple sclerosis (RRMS) in a Phase 3 study (ADVANCE). Patients were randomized to receive SC injections of placebo (n = 500), 125 mcg every-2-weeks (n = 512), or 125 mcg every-4-weeks (n = 500) for 1 year, and then active treatment in the second year. Steady state 4-week AUC (AUCss) was derived for each individual based on sparse pharmacokinetic (PK) sample and a population PK model. Several longitudinal count models, including marginal, mixed effect, and mixture models, were compared to explore the relationship between AUCss and Gd+ lesion count (or T2 lesion count). A mixture model which divided subjects into two subpopulations by low and high baseline lesion activity was found to yield best goodness-of-fit for the data. In this model, the point estimate and 95 % CI for drug effect slope on log(λ) are −0.0256 (−0.0304, −0.0216) for Gd+ lesion and −0.0147 (−0.0170, −0.0124) for T2 lesion. This suggested that reduction of Gd+ lesion (or T2 lesion) count over time is significantly related to SC peginterferon β-1a exposure, and that the increased reduction lesion count with the every-2-week regimen versus the every-4-week regimen was driven by the higher exposure achieved in that treatment arm (mean Gd+ lesion count 0.2 and 0.7 at Year 2, respectively). The every-2-week regimen produced an exposure range that was close to the plateau range of the exposure–response curve, supporting its selection as the regulatory approved dosage. Electronic supplementary material The online version of this article (doi:10.1007/s10928-016-9477-x) contains supplementary material, which is available to authorized users.

Therapy for asthma often includes the combined use of glucocorticoids and leukotriene receptor antagonists. The short-term, combined effects of these drugs on cytokine secretion and lymphocyte proliferation are ill-defined. The aim of this study was to analyze allergen and mitogen-induced cytokine secretion and lymphocyte proliferation in asthmatics and to determine the effect of combined therapy on these immune responses. Peripheral blood mononuclear cells were isolated from mild, persistent adult asthmatics (n = 28) and analyzed for cat allergen (Fel d 1) and mitogen (phytohemagglutinin) induced IL-13 and IFN-gamma secretion and lymphocyte proliferation. Samples were analyzed before and after 10 days of therapy with oral zafirlukast, prednisone (0.5 mg/kg/day), and inhaled budesonide (1600 mcg/day). Both Fel d 1 and mitogen stimulation resulted in IL-13 and IFN-gamma secretion. Combination drug therapy resulted in a significant decrease in allergen-induced IFN-gamma secretion (p = 0.018) and allergen-specific lymphocyte proliferation (p = 0.02), while IL-13 secretion was unchanged (p = 0.109). This study indicates a role for Th1 cytokines as well as Th2 cytokines in the allergic response.

Background Subcutaneous peginterferon beta-1a provided clinical benefits at Year 1 (placebo-controlled period) of the 2-Year Phase 3 ADVANCE study in relapsing-remitting multiple sclerosis (RRMS). Here we report the effect of peginterferon beta-1a on brain magnetic resonance imaging (MRI) lesions, and no evidence of disease activity (NEDA; absence of clinical [relapses and 12-week confirmed disability progression] and MRI [gadolinium-enhancing, and new or newly-enlarging T2 hyperintense lesions] disease activity) during Year 1. Methods RRMS patients (18–65 years; Expanded Disability Status Scale score ≤5) were randomized to double-blind placebo or peginterferon beta-1a 125 μg every 2 or 4 weeks. Sensitivity analyses of last observation carried forward and composite disease activity (using minimal MRI allowance definitions) were conducted. Results 1512 patients were randomized and dosed (placebo n = 500; peginterferon beta-1a every 2 [n = 512] or 4 [n = 500] weeks). Every 2 week dosing significantly reduced, versus placebo and every 4 week dosing, the number of new or newly-enlarging T2 hyperintense lesions at Weeks 24 (by 61% and 51%, respectively) and 48 (secondary endpoint; by 67% and 54%, respectively); all p