A minimal physiologically based pharmacokinetic model that predicts anti-PEG IgG-mediated clearance of PEGylated drugs in human and mouse.

Circulating antibodies that specifically bind polyethylene glycol (PEG), a polymer routinely used in protein and nanoparticle therapeutics, have been associated with reduced efficacy and increased adverse reactions to some PEGylated therapeutics. In addition to acute induction of anti-PEG antibodies (APA) by PEGylated drugs, typically low but detectable levels of APA are also found in up to 70% of the general population. Despite the broad implications of APA, the dynamics of APA-mediated clearance of PEGylated drugs, and why many patients continue to respond to PEGylated drugs despite the presence of pre-existing APA, remains not well understood. Here, we developed a minimal physiologically based pharmacokinetic (mPBPK) model that incorporates various properties of APA and PEGylated drugs. Our mPBPK model reproduced clinical PK data of APA-mediated accelerated blood clearance of pegloticase, as well as APA-dependent elimination of PEGyated liposomes in mice. Our model predicts that the prolonged circulation of PEGylated drugs will be compromised only at APA concentrations greater than ~500 ng/mL, providing a quantitative explanation to why the effects of APA on PEGylated treatments appear to be limited in most patients. This mPBPK model is readily adaptable to other PEGylated drugs and particles to predict the precise levels of APA that could render them ineffective, providing a powerful tool to support the development and interpretation of preclinical and clinical studies of various PEGylated therapeutics.

Comparison of technetium-99m and iodine-123 imaging of thyroid nodules: correlation with pathologic findings.

Three hundred and sixteen patients with solitary or dominant thyroid nodules were imaged both with technetium-99m- (99mTc) pertechnetate and iodine-123 (123I). The images were preferred, but differences were small and in 27%-58% of the cases there was no difference in quality between the two radionuclides. Discrepancies between 99mTc and 123I images were found in 5%-8% of cases, twice as often in multinodular goiters as in single nodules. Cytologic/histologic examination was performed on all nodules but no correlation was found between the pathology and the type of discrepancy. Twelve carcinomas were found (4%) but none in nodules showing a discrepancy. There was great variation among the observers about the preference for radionuclides and about the existence or type of discrepancies. The slightly better overall quality of 123I scans is probably not of diagnostic significance and does not justify the routine use of 123I instead of 99mTc. Routine reimaging of 99mTc hot nodules with radioiodine for cancer detection does not appear to be necessary.

Comparison of wound healing between chopped mode-superpulse mode CO2 laser and steel knife incision.

The healing of surgical incisions made with the steel knife and CO2 laser chopped wave mode (ChW) or rapid superpulse (RSP) mode were compared using histologic parameters and breaking strength of the scars on postoperative day 14. Using a miniature pig model the Sharplan 1100 laser incisions were made with an average power of 15 W and power density of 7.68 kW/cm2. Histological sections on postoperative day 14 revealed the knife scar measured .49 mm, was hypocellular, and contained visible bundles of collagen fibers. Both CO2 laser scars were less mature, the ChW scar measured 1.04 mm, the RSP scar measured 1.37 mm, and both contained cellular granulation tissue without visible collagen fibers. The breaking strength of the scars was measured with a tensiometer. Laser wounds were weaker than the knife wound. Scheffe test for variables was significant at P = .01 between the two laser modes and the knife. No significant difference was noted in the breaking strengths of incisions made with the chopped mode and superpulse mode.