Detaljerad miljöinformation

According to the European Medicines Agency guideline on environmental risk assessment of medicinal products (EMA/CHMP/SWP/4447/00), use of sacituzumab govitecan is unlikely to represent a risk for the environment, because the predicted environmental concentration (PEC) at the time of registration was below the action limit 0.01 μg/L.

Sacituzumab govitecan contains a monoclonal antibody, which can be categorized as a protein and is therefore exempted from the ERA-guideline.  The environmentally relevant portion is the small molecule SN-38 connected by a linker, which is a small percentage of the compound and the calculated PECsw for SN-38 is approximately 2-fold below the EMA action limit of 0.01 μg/L. No further investigations on the environmental fate and effects detailed in Phase II Tier A of the EMA guidance document are required (EMEA/CHMP/SWP/4447/00 corr 2).

An estimation of the PECsw and evaluation of the octanol water coefficient for SN-38 – the cytotoxic payload of sacituzumab govitecan - is considered the most appropriate approach to judge the environmental risk of the antibody drug conjugate. Information on the partition coefficient for SN-38 (predicted and experimentally determined with the shake flask method) was retrieved from relevant databases and the literature. The log Kow has been reported in the literature to be 2.65 (Fang et al, 2018, Wu et al, 2019).  Since all values are below the trigger value (log Kow >4.5) no further screening for persistence, bioaccumulation and toxicity is warranted.

It can be concluded that it is unlikely that the use of sacituzumab govitecan results in significant risk to the environment.

Conclusion: Use of amino acids/peptides/proteins has been considered to result in insignificant environmental impact and the small molecule portion exposure was below the EMA action limit to trigger an ERA.

Predicted Environmental Concentration (PEC)

PEC is calculated according to the following formula:

PEC (μg/L) = (A*10⁹*(100-R))/(365*P*V*D*100) = 1.37*10^-6*A(100-R)

PEC (μg/L) = (0,238*10⁹*(100-0))/(365*10000000*200*10*100) = 1.37*10^-6*0,238(100-0)PEC = 0.0000326 μg/L

Where: A = 0,238 kg (total sold amount API in Sweden year 2022, internal data (data from IQVIA not available)). Reduction of A may be justified based on metabolism data. R = 0 % removal rate (due to loss by adsorption to sludge particles, by volatilization, hydrolysis or biodegradation) = 0 if no data is available. (If R ‡0 this should be justified under the degradation section).  P = number of inhabitants in Sweden = 10 *106V (L/day) = volume of wastewater per capita and day = 200 (ECHA default) (Ref. I). D = factor for dilution of waste water by surface water flow = 10 (ECHA default) (Ref. I).

Predicted No Effect Concentration (PNEC)

Not available.

Environmental risk classification (PEC/PNEC ratio)

Not available.

Degradation

The sacituzumab govitecan antibody (Ab) is the major component of the medicinal product and unlikely to result in a significant risk to the environment since proteins of biological origin are abundant in the biosphere and are, if present in a soluble form in the environment, rapidly inactivated and degraded in the wastewater treatment facility. In the body SN-38, the topoisomerase inhibitor and the active metabolite of the chemotherapeutic agent irinotecan, will be hydrolysed by endogenous esterases from the linker (CLA2) and CLA2 remains covalently bound to the Ab. Thus, it is unlikely that SN-38 bound to the linker (SN-38-CLA2) will enter the environment at any meaningful concentration. An environmental risk assessment for SN-38-CLA2 is not appropriate. In addition, assessment of an environmental risk for CLA2 alone was not considered relevant. The toxicity data obtained with sacituzumab govitecan reflect the known toxicity profile of SN-38, no additional toxicity was observed indicating any toxicity of the linker CLA2 itself.

In addition, the calculated PECsw for SN-38 is approximately 2-fold below the action limit of 0.01 μg/L. No further investigations on the environmental fate and effects detailed in Phase II Tier A of the EMA guidance document are required.

Biotic degradation

Not available.

Abiotic degradation

Not available.

References

• Committee for Medicinal Products for Human Use (CHMP); Guideline on the Environmental Risk Assessment of Medicinal Products for Human Use. 1 June 2006, Ref EMEA/CPMP/SWP/4447/00.

• Trodelvy Environmental Risk Assessment non-GMO

• Trodelvy Summary of Product Characteristics.

• Fang YP, Chuang CH, Wu YJ, Lin HC and YC Lu. SN38-loaded <100 nm targeted liposomes for improving poor solubility and minimizing burst release and toxicity: in vitro and in vivo study. Int J Nanomedicine. 2018;13:2789–2802.

• Wu C, Zhang Y, Yang D, Zhang J, Ma J, et al. Novel SN38 derivative-based liposome as anticancer prodrug: an in vitro and in vivo study. Int J Nanomedicine. 2019;14:75–85.