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• W2779391059 abstract "Over the last 20 years, biologic agents (tumor necrosis factor antagonists and, more recently, monoclonal antibodies with other targets) have been instrumental in improving outcomes among patients with inflammatory bowel disease. Although highly effective, approximately 40% of those treated with infliximab and adalimumab lose response within 12 months,1 and a further 10–20% annually thereafter.2 Similar rates of loss of response have been observed with ustekinumab, a relatively new monoclonal antibody targeting the p40 subunit of IL-12/23.3, 4 Median time to loss of response for infliximab, adalimumab, and ustekinumab is 13, 8.3, and 6.7 months, respectively.4, 5 Accordingly, understanding mechanisms responsible for, and in turn managing loss of response is a key issue. Loss of response is frequently associated with reduced drug levels, commonly measured as trough concentrations in the serum. The level of a drug depends upon the balance between the bioavailability and its subsequent clearance. The bioavailability of intravenously administered biological agents is assured, and adherence to this is readily assessable. However, the situation with subcutaneously administered therapies is quite different; interindividual variance in lymphatic uptake and drug catabolism at the injection site contributes to rates of bioavailability as low as 64% with adalimumab, 53% golimumab, and 57% ustekinumab.6 Non-adherence is well recognized, but that is usually assessable by evaluating prescription-filling or by observing undetectable drug levels.7 Bioavailability aside, attention has largely focused on increased clearance of the drug as the reason for low drug levels. Clearance across individuals may vary according to factors that include gender or body mass index or to inherent proteolytic clearance mechanisms such as the activity of the salvage Bramble receptor system.8, 9 However, their relative influence is likely to be small and, while they might impact primary response to the drugs, they are unlikely to contribute to secondary loss of response. Inflammatory burden and immunogenicity are two significant drivers of increased drug clearance. The former acts via a “consumptive” process leading to low drug levels (the so-called “antigen sink”) or via direct drug loss from an inflamed gut. The latter occurs largely via the development of antidrug antibodies.9 Therapeutic strategies in the face of LOR related to subtherapeutic drug levels have, therefore, been to minimize clearance via the use of concomitant immunomodulation and to increase dosage. Both of these approaches have strong evidence of success, further increasing the already rising cost of biologic agents to the health care system.10 A new mechanism underpinning for subcutaneously delivered biological therapies has been identified in the study by de Jong et al.11 Although initially exploring the possibility of biologic-agent cost-saving through reuse, this study brings to light the issue of incorrect medication storage. Fifty patients with immune-mediated inflammatory diseases who were dispensed 276 prefilled golimumab syringes were prospectively included. Temperature of golimumab storage was monitored via telemetric transmission of temperature data every 5 min from the packaging over a prolonged time period. Alarmingly, 88% of golimumab injectors were stored at temperatures outside the recommended range; 12% below 0°C and a staggering 29% above 8°C for more than 1 week before use. While the investigators did not examine efficacy or viability of the drugs, current recommendations are that such agents should be discarded under either of these conditions. Conformational changes in the complex protein structure of biologics as a consequence of freeze–thawing or prolonged storage at elevated temperatures may lead to denaturation, irreversible formation of protein aggregates and loss of biological activity.12-14 Theoretically, this may lead to a higher chance of the development of antidrug antibodies with consequent increased clearance following further doses of the drug.15-17 It might also lead to measurement of drug in the serum that is biologically inactive, and, in the setting of loss of response, the erroneous conclusion of “therapeutic levels.” Indeed, the close association of levels with efficacy that has been established for infliximab is often not seen with adalimumab.18 Perhaps the use of poorly stored adalimumab of reduced biological activity might explain this lack of association. However, none of these scenarios were examined in the report by de Jong et al., but clearly warrants further work. Subcutaneous biologics such as adalimumab, golimumab and ustekinumab should be refrigerated during storage at a temperature of 2–8°C and be discarded if frozen, even if subsequently thawed. As de Jong et al. point out, adalimumab remains stable at temperatures up to 25°C for 14 days according to its manufacturer, but ustekinumab carries similar stability recommendations as golimumab. Their study was conducted in the Netherlands where it might be anticipated that refrigeration is readily available, and that the drug is dispensed with specific storage instructions and warnings. Comparative research using a range of subcutaneous biologics coupled to therapeutic drug monitoring and clinical outcomes conducted in developing countries where access to high quality cold-chain infrastructure may be lacking is needed. On face value, given the high societal cost of biologic therapies and the potential for savings, redistribution and reuse of unused drug is an attractive concept. The study by de Jong et al. clearly demonstrates that under current conditions such a policy would be inappropriate. Taking things further, given such real-life storage inconsistencies, should we be reevaluating the way high-cost medication is supplied to patients? Pharmacists have a responsibility to ensure safe dispensing of medications, but in view of the data by de Jong et al., more clearly needs to be done. At a minimum, pharmacists and nurses who care for patients treated with biologics must stress the importance of storage conditions through adequate and ongoing education. Temperature-controlled kits should be dispensed with drug for transport storage. Patients should consider testing their refrigerators working temperature, understanding that this can vary between shelves. If home storage conditions are inadequate, alternative strategies, such as the patient's primary care provider storing and administering the drug or a courier service maintaining cold-chain, could be implemented. In addition, temperature-sensitive warning devices could be incorporated into packaging. In conclusion, de Jong et al. have identified the reality of patient adherence to storage guidelines. The potential implications to loss of efficacy and increased immunogenicity with subsequent enhanced drug clearance and lower serum concentrations are significant, and highlight an additional, but avoidable cause for loss of response to subcutaneously delivered biological agents." @default.
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• W2779391059 date "2017-12-28" @default.
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• W2779391059 title "Inadequate storage of subcutaneous biological agents by patients with inflammatory bowel disease: Another factor driving loss of response?" @default.
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