Do Inadequate Storage Practices Play a Role in Loss of Response to Subcutaneous Biologic Agents?

A recent study in the Journal of Gastroenterology and Hepatology, by Marin J. de Jong, MD, and colleagues, has identified incorrect storage practices of subcutaneously administered biologic therapies as a potential factor driving secondary loss of response (LOR) to subcutaneously delivered anti—tumor necrosis factor (anti-TNF) drugs. The study, set in the Netherlands, sought to assess patients’ attitudes about redistributing unused, subcutaneously administered biologic drugs, which could allow potential cost savings for the health system. However, the study unexpectedly found alarming storage inconsistencies and patient nonadherence to storage guidelines for these drugs.

An accompanying editorial by C. Rentsch, GCPharmPract, and colleagues, notes that the potential implications for 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 LOR to subcutaneously delivered biological agents.

Approximately 40% of patients treated with the anti-TNF agents infliximab and adalimumab experience LOR within 12 months, and a further 10% to 20% per year lose response thereafter. LOR is frequently associated with reduced drug levels, which are often attributed to antidrug antibodies (ADAs) and inflammatory burden. Thus, the response has been to treat LOS with concomitant immunomodulation and an increase in dosage—both of which have been successful, further increasing the rising cost of therapy with biologic agents to the healthcare system.

The researchers followed 50 patients who used golimumab for different inflammatory disease indications at Maastricht University Medical Center. Patients received golimumab injectors in a sealed bag containing a validated temperature sensor that measured temperature every 5 minutes. Patients were asked to store their medication as usual. Deviations from the recommended range were defined as any duration below 0°C and greater than 30 minutes below 2°C or above 8°C.

“Alarmingly, 88% of golimumab injectors were stored at temperatures outside the recommended range,” the editorial notes, “12% below 0°C and a staggering 29% above 8°C for more than 1 week before use.”

Although the researchers did not examine the efficacy or viability of the drugs, current recommendations are that such agents should be discarded under either of these conditions because of changes in the complex protein structure as a consequence of freeze-thawing or prolonged storage at elevated temperatures that may lead to denaturation, irreversible formation of protein aggregates, and loss of biological activity.

The finding raises concerns regarding the effectiveness of subcutaneously administered biologics in patients with immune-mediated inflammatory disease. Theoretically, the poor storage practices exposed by the study may lead to a higher chance of the development of ADAs with consequent increased drug clearance following further doses of the drug.

Furthermore, the issue might also lead to measurement of drug in the serum that is biologically inactive, and, in the setting of LOR, the erroneous conclusion of “therapeutic levels.”

Although de Jong and colleagues’ study did not examine these scenarios, their findings clearly suggest that further work is warranted, the researchers state.

“Taking things further, given such real-life storage inconsistencies, should we be reevaluating the way high-cost medication is supplied to patients?” the editorial asks. “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.”

They suggest the following:

• Temperature-controlled kits should be dispensed with drugs for transport storage.
• Patients should consider testing their refrigerators’ working temperature, which 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 drug delivery standards, could be implemented.
• Temperature-sensitive warning devices could be incorporated into packaging.