Efficacy, Safety and Pharmacokinetics of Oral NKTR-118 in Patients with Opioid-Induced Constipation: Results of a Randomized, Double-blind, Placebo-controlled Phase 2 Study

Webster, Lynn R.; Blonsky, R.; Matz, Paul G.; Levinsky, D.; Martz, René; Dhar, Sunita; Neumann, Theresa; Eldon, Michael A.; Patrick, Teressa

doi:10.14309/00000434-200910003-00466

Cited by 5 publications

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“…Since then PEGylation has gained increasing popularity as a means to prolong the duration of action of biopharmaceuticals and to prevent the occurrence of both neutralizing antibodies and autoantibodies that may compromise the pharmacodynamic properties of the compound or lead to an adverse drug reaction. More recently, PEGylation has also been applied to traditional small molecule drugs, such as naloxol and irinotecan, to improve their pharmacokinetic profiles. Despite the well-documented benefits that accrue from PEGylation, there have been some reports of safety issues in animal studies due to the organ accumulation of PEG, particularly in the kidney, and of antibodies being generated against PEGylated proteins. , With respect to the immunogenicity of PEGylated proteins in man, where clinical trial data allow a direct comparison between a native and PEGylated form (as is the case for IL2, IFN-γ, and asparaginase, among others) the reduction, but not complete abrogation, of neutralizing antibodies is seen .…”

Section: Discussionmentioning

confidence: 99%

Evidence for Metabolic Cleavage of a PEGylated Protein in Vivo Using Multiple Analytical Methodologies

et al. 2012

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PEGylation of therapeutic proteins is commonly used to extend half-lives and to reduce immunogenicity. However, reports of antibodies toward PEGylated proteins and of poly(ethylene glycol) (PEG) accumulation suggest that efficacy and safety concerns may arise. To understand the relationship among the pharmacology, immunogenicity, and toxicology of PEGylated proteins, we require knowledge of the disposition and metabolic fate of both the drug and the polymer moieties. The analysis of PEG by standard spectrophotometric or mass spectrometric techniques is problematic. Consequently, we have examined and compared two independent analytical approaches, based on gel electrophoresis and nuclear magnetic resonance (NMR) spectroscopy, to determine the biological fate of a model PEGylated protein, 40KPEG-insulin, within a rat model. Both immunoblotting with an antibody to PEG and NMR analyses (LOD 0.5 μg/mL for both assays) indicated that the PEG moiety remained detectable for several weeks in both serum and urine following intravenous administration of 40KPEG-insulin (4 mg/kg). In contrast, Western blotting with anti-insulin IgG indicated that the terminal half-life of the insulin moiety was far shorter than that of the PEG, providing clear evidence of conjugate cleavage. The application of combined analytical techniques in this way thus allows simultaneous independent monitoring of both protein and polymer elements of a PEGylated molecule. These methodologies also provide direct evidence for cleavage and definition of the chemical species present in biological fluids which may have toxicological consequences due to unconjugated PEG accumulation or immunogenic recognition of the uncoupled protein.

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Section: Discussionmentioning

confidence: 99%

Evidence for Metabolic Cleavage of a PEGylated Protein in Vivo Using Multiple Analytical Methodologies

et al. 2012

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“…Naloxone has been described as the “gold standard” opioid antagonist, used to reverse the effects of opioids . It is a competitive antagonist with no evidence of tolerance or dependence developing.…”

Section: Introductionmentioning

confidence: 99%