What about monoclonal antibodies?
There are two separate but related concepts regarding monoclonal antibodies (mABs) and why they’ve generally been excluded from the excretion table on this website.
What's on the list?
Only four mABs were included the 2010 NIOSH HD list:
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alemtuzumab (later removed)
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gemtuzumab ozogamicin
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ibritumomab tiuxetan
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tositumomab (withdrawn from market in 2014)
By 2016, ado-trastuzumab emtansine, brentuximab vedotin, and pertuzumab were added, with alemtuzumab being removed and the other two eliminated due to market availability. Except for pertuzumab, the remaining mABs on the 2016 list are antibody-drug conjugates (ADCs) (where a payload drug is attached to the antibody). ADCs pose a particular quagmire for determining whether it is hazardous as data for the freely excreted drug portion may be difficult to obtain. In general, if the conjugated drug is hazardous, then the conjugated mAB is also considered hazardous.
Despite their widespread ubiquitous use, rituximab and cetuximab are not on these lists. Why is that?
The initial NIOSH HD list was created by using a number of different sources. Subsequently, NIOSH began creating their own list with information from drug manufacturers, AFHS, IARC, and Drugbank. And after a public comment period, the finalized list is then published. The proposed 2018 list was never published, as of July 2020, NIOSH is still taking public comment on the 2020 list and related publications.
Size Matters
One of the reasons mABs have not been included involves the size of the molecule. Whereas chemotherapy agents are considered "small molecules" in the 100-500 Da (Dalton) range (see Figure 1 below), mABs (which are immunoglobulins) are huge (Wang W, Wang EQ, & Balthasar JP, 2008). Research into transdermal delivery methods has shown that protein molecules are simply too large to penetrate the stratum corneum. For this reason, the attempt to develop a transdermal form of insulin, (with a size of approximately 5,000 Da), has been disappointingly unsuccessful (Szunerits & Boukerroub, 2018). Banerjee and colleagues state: "...drugs such as peptides, proteins, and nucleic acids cannot be administered through the skin..." (Banerjee, A. et al 2017)
Rituximab, for example, is 143,860 Da. (Figure 2.) Since the primary route of HD absorption for healthcare workers is dermal, these large molecules are not believed to be absorbable. Typically, transdermal medications (Figure 3) fall under the “500 Dalton Rule.” (Bos JD & Meinardi M, 2000). The large size of mABs means that skin contact would not lead to human uptake. So while these drugs may meet the ASHP/NIOSH definition of being hazardous, it is generally believed they cannot be absorbed via contact.
However, there is still concern for potential inhalation of aerosols that could occur when compounding some mABs without using a CSTD. Animal models show that measurable serum levels can be achieved via mAB inhalation although more research is needed (de Lemos ML et al, 2017; Guilleminault L. et al, 2014).
Lastly, we should also remember that the ability to be absorbed is different from a drug's hazardous properties. As an analogy, putting cesium-131 behind 18 inches of lead does not make it less radioactive, just less hazardous to humans. So while direct dermatologic absorption of these drugs is unlikely, it does not preclude absorption via mucous membranes or non-intact skin.
Figure 1 Common IV Antineoplastic agents
Figure 2 Common mABs
Figure 3 Transdermal Drugs
Source: www.drugbank.ca
Where do they go?
The second related question has to do with excretion.
While a detailed discussion on Absorption, Distribution, Metabolism and Excretion (ADME) is beyond the scope of this website, small molecules are typically excreted via the renal or hepatobiliary systems contributing to drug and/or metabolites in urine and stool (or bile). Oral agents tend to have higher elimination via the GI tract whereas IV agents are more often excreted via the kidneys.
Metabolism and excretion of mABs is quite complex and involves the reticuloendothelial system (RES) which is responsible for “recycling” immunoglobulins. Clearly, we would not want large protein molecules being squeezed through our glomeruli! The RES uses immune cells such as macrophages and monocytes with Fc IgG receptors to bind with the IgG mABs. Monoclonal antibodies are also eliminated via intracellular catabolism. In addition, the type of mAB plays a role in elimination: murine-based mABs (e.g. blintumomab) are rapidly eliminated, with short half-lives (i.e., 24 hours). Conversely, fully human mABs can have a half-life of 3 or more weeks (Wang, Wang & Balthasar, 2008, Nature, 84(5)).
The challenge for HD safety is understanding the risk that each mAB might pose and the potential mechanism for exposure. As we continue to see more and more mABs in oncology, we will hopefully gain more understanding about the necessary precautions.
What about subcutaneous mABs?
Although NIOSH has yet to make an official recommendation, when a mAB is combined with hyaluronidase (which allows for rapid subcutaneous absorption), the ability of the drug to be absorbed changes. Hyaluronidase temporarily breaks down membranes in subcutaneous tissues. How this affects the layers of the epidermis is unclear, but if it is determined that mABs combined with it could potentially be absorbed, they would need to be handled as an HD.