Aaps J
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Randomized Controlled Trial Multicenter Study
Population-based efficacy modeling of omalizumab in patients with severe allergic asthma inadequately controlled with standard therapy.
Omalizumab, a recombinant humanized monoclonal antibody, is the first approved anti-immunoglobulin E (IgE) agent for the treatment of subjects with moderate to severe persistent allergic asthma that are inadequately controlled by the standard of care. The objective of this study was to quantitatively characterize relationships between serum free IgE and pulmonary function (as measured by forced expiratory volume in 1 s [FEV1]) as well as serum free IgE and airway inflammation (as measured by fractional exhaled nitric oxide [FeNO]) using population-based efficacy models. ⋯ Results from the efficacy models further confirmed the current omalizumab dosing rationale based on the mean target free IgE level of 25 ng/ml and quantified the variability for the target. In addition, the resulting population models could be used to predict population FEV1 or FeNO response for omalizumab and/or other anti-IgE therapeutics for which PK-IgE models are constructed.
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Motor complications of Parkinson's disease (PD) are a consequence of pulsatile dopaminergic stimulation from standard oral levodopa therapy. Levodopa-carbidopa intestinal gel (LCIG) is infused continuously via an intrajejunal percutaneous gastrostomy tube. This was the first study designed to characterize the full pharmacokinetic profiles of levodopa, carbidopa, and levodopa metabolite, 3-O-methyldopa (3-OMD) with 16-h LCIG infusion. ⋯ Continuous intrajejunal LCIG infusion maintained stable plasma levodopa levels over 16 h. Consistent exposure has been shown to reduce motor and nonmotor complications associated with oral medications. LCIG was well tolerated, consistent with previous reports.
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Randomized Controlled Trial Multicenter Study
Population analyses of efficacy and safety of ABT-594 in subjects with diabetic peripheral neuropathic pain.
ABT-594, a neuronal nicotinic acetylcholine receptor ligand, is 30- to 100-fold more potent than morphine in animal models of nociceptive and neuropathic pain. Efficacy and safety of ABT-594 in subjects with painful diabetic polyneuropathy was evaluated in a phase 2 study. The objective of this work was to use a nonlinear mixed effects model-based approach for characterizing the relationship between dose and response (efficacy and safety) of ABT-594. ⋯ ABT-594 ED(50) values (improvement in 50% of subjects) for improvement in pain scores of ≥1, ≥2, and ≥3 were 50, 215, and 340 μg, respectively, for the average number of days (33) on treatment. The rank order of ED(50) values for AEs was nausea, vomiting, dizziness, headache, and abnormal dreams; nicotine users were less sensitive to AEs. Population pharmacodynamic models developed to characterize the improvement in pain score and incidence of adverse events indicate an approximately twofold separation between the ED(50) values for efficacy and AEs.