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.

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Objective: To review the pharmacological characteristics, clinical evidence, and place in therapy of voxelotor for the treatment of sickle cell disease (SCD). Data Sources: A comprehensive literature search of PubMed (1966 to April 2020) was conducted. Key search terms included GBT440, sickle cell, and voxelotor. Other sources were derived from bibliographies of articles, product labeling, manufacturer’s website, and news releases. ClinicalTrials.gov was searched for additional studies. Study Selection and Data Extraction: All English-language articles identified from the data sources were reviewed and evaluated. Case reports/series and phase 1 through 3 clinical trials were included. Data Synthesis: SCD is an inherited disorder associated with significant morbidity and early mortality. Three medications approved for SCD reduce SCD-associated complications but do not selectively ameliorate the underlying disease. Voxelotor is a novel agent that targets the pathophysiology of SCD. A phase 3 trial reported an increase in mean Hb level from baseline for voxelotor compared with placebo (1.1 vs −0.1 g/dL; P < 0.001). Voxelotor is generally well tolerated, with common adverse effects including headache, diarrhea, nausea, and arthralgia. Relevance to Patient Care and Clinical Practice: Voxelotor may be considered for patients with SCD who have continued anemia and hemolysis despite being on maximum tolerated dose of hydroxyurea or in those who are hydroxyurea intolerant. Voxelotor is costly; therefore, both cost and benefit should be weighed before prescribing. Conclusion: Voxelotor appears to be safe and effective as monotherapy or in combination with hydroxyurea for patients with SCD who are 12 years of age and older.

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Objectives To evaluate changes in acute health services use of Senior PharmAssist participants. Design Retrospective analysis. Setting Community‐based, nonprofit program in Durham County, North Carolina. Participants Adults aged 60 and older with income of 200% of the federal poverty level or less who enrolled in the Senior PharmAssist program (N = 191) between August 1, 2011, and March 15, 2017. Intervention Medication therapy management (MTM), customized community referrals, Medicare insurance counseling, and medication copayment assistance provided by Senior PharmAssist. Measurements Primary outcomes were self‐reported emergency department (ED) visits and hospital admissions in the previous year, assessed at baseline and every 6 months for up to 2 years. Results Mean number of ED visits declined over time (0.83 visits per year at baseline to 0.53 visits per year at 24 months, P = .002), as did the percentage of participants reporting an ED visit in the past year (49% at baseline to 31% at 24 months, P = .003). Mean hospital admissions also decreased (0.56 admissions per year at baseline to 0.4 admissions per year at 24 months, P = .02). There was no significant change in percentage of participants reporting a hospital admission in the past year (33% at baseline to 25% at 24 months, P = .23). Conclusion Older adults who enrolled in a community‐based program that helps them manage medications, connect with community resources, and overcome barriers to medication access experienced reductions in acute health services use. J Am Geriatr Soc 66:2394–2400, 2018.

Background: Minibeam radiation therapy is an experimental radiation therapy utilizing an array of parallel submillimeter planar X-ray beams. In preclinical studies, minibeam radiation therapy has been shown to eradicate tumors and cause significantly less damage to normal tissue compared to equivalent radiation doses delivered by conventional broadbeam radiation therapy, where radiation dose is uniformly distributed. Methods: Expanding on prior studies that suggested minibeam radiation therapy increased perfusion in tumors, we compared a single fraction of minibeam radiation therapy (peak dose:valley dose of 28 Gy:2.1 Gy and 100 Gy:7.5 Gy) and broadbeam radiation therapy (7 Gy) in their ability to enhance tumor delivery of PEGylated liposomal doxorubicin and alter the tumor microenvironment in a murine tumor model. Plasma and tumor pharmacokinetic studies of PEGylated liposomal doxorubicin and tumor microenvironment profiling were performed in a genetically engineered mouse model of claudin-low triple-negative breast cancer (T11). Results: Minibeam radiation therapy (28 Gy) and broadbeam radiation therapy (7 Gy) increased PEGylated liposomal doxorubicin tumor delivery by 7.1-fold and 2.7-fold, respectively, compared to PEGylated liposomal doxorubicin alone, without altering the plasma disposition. The enhanced tumor delivery of PEGylated liposomal doxorubicin by minibeam radiation therapy is consistent after repeated dosing, is associated with changes in tumor macrophages but not collagen or angiogenesis, and nontoxic to local tissues. Our study indicated that the minibeam radiation therapy’s ability to enhance the drug delivery decreases from 28 to 100 Gy peak dose. Discussion: Our studies suggest that low-dose minibeam radiation therapy is a safe and effective method to significantly enhance the tumor delivery of nanoparticle agents.