Safety in regional blocks for ophthalmic procedures.

Abstract

<h3>Objective:</h3> To describe the population pharmacokinetics (PK) of levodopa and carbidopa following subcutaneous (SC) infusion with ND0612, with and without oral therapy, including associated interindividual variability and residual unexplained variability. <h3>Background:</h3> ND0612 is in development as the first continuous SC levodopa/carbidopa infusion to reduce motor complications in patients with Parkinson’s disease (PD). Several PK studies have been performed and have confirmed stable levodopa and carbidopa plasma levels following SC infusion with ND0612. <h3>Design/Methods:</h3> Two integrated population PK models (for levodopa and for carbidopa) were developed using data from two Phase I studies of ND0612 (Studies 004 and 005) in healthy volunteers and PD patients, respectively. The predictive performance of each model was then tested using data from a third Phase I study in healthy volunteers (Study 114). Model refinement was performed using aggregated data from the 3 studies and will be continually updated as more PK data from ongoing Phase III studies becomes available. <h3>Results:</h3> Levodopa and carbidopa population PK were both adequately described by a one compartment disposition model with first-order oral and SC absorption. Levodopa had parallel dopa decarboxylase (DDC) and COMT elimination from the central compartment, in which the inhibition of apparent DDC-mediated clearance was driven by carbidopa plasma concentrations. Carbidopa had linear elimination. Exploration of covariates revealed that age had a significant effect on apparent clearance and apparent volume of distribution for both carbidopa and levodopa, even after accounting for body weight differences; both parameters decreased with increasing age. <h3>Conclusions:</h3> Model diagnostics for the carbidopa and levodopa population PK models indicated a satisfactory predictive performance, supporting their usability to derive individual predictions of exposure to be used in future pharmacokinetic-pharmacodynamic analyses. <b>Disclosure:</b> Tal Birnberg has received personal compensation for serving as an employee of NeuroDerm. Giovanni Smania has received personal compensation for serving as an employee of Pharmetheus AB. Marcus Björnsson has received personal compensation for serving as an employee of Pharmetheus. Marcus Björnsson has received personal compensation in the range of $100,000-$499,999 for serving as a Consultant for Pharmetheus. Niclas Jonsson has received personal compensation for serving as an employee of Pharmetheus. Dr. Case has received personal compensation for serving as an employee of NeuroDerm. Sheila Oren, MD, MBA has received personal compensation for serving as an employee of Neuroderm. Sheila Oren, MD, MBA has received personal compensation in the range of $0-$499 for serving as a Consultant for Neuroderm. Liat Adar has received personal compensation for serving as an employee of Neuroderm. Mats Karlsson has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Pharmetheus AB. Mats Karlsson has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Springer. The institution of Mats Karlsson has received research support from Swedish Research Council, FDA, IMPAACT, TB Alliance, NIH, Roche, Merck, GSK.