Brentuximab vedotin

Detailed information

General information about assessment reports

Since 2006, an Environmental Risk Assessment (ERA) for the active pharmaceutical substance shall accompany an application for a marketing authorisation in EU for a medicinal product for human use. Parts of environmental data can be found in the public investigation report (PAR/EPAR for medicinal product through a centralized procedure). Since the benefit/risk assessment for human medicinal products at present does not include environmental effects, an update of the environmental risk assessment is not required for renewals of marketing authorizations. There is thus no requirement for companies to stay informed about the development of their substances from an environmental point of view and consequently to update the environmental risk assessment as new data are published.

Brentuximab vedotin has only undergone a phase I study according to regulatory requirements for environmental risk assessments (European Medicines Agency, EMA: Committee for Medicinal Products for Human Use (CHMP). Guideline on the Environmental Risk Assessment of Medicinal Products for Human Use. 1 June 2006.) A phase I study includes data on bioaccumulation and calculates the concentration of brentuximab vedotin in the environment (PEC_{Surface water)}. If specified limit values are not exceeded, the company does not need to conduct a phase II study that includes data on toxicity and persistence and calculation of risk based on PEC/PNEC.

Assessment report for Adcetris 2012

Assessment report for Adcetris (brentuximab vedotin), 19 July 2012, EMA/702390/2012.

Hazard

Persistence: No data.

Bioaccumulation: No data.

Toxicity: No data.

"A PBT assessment has not been completed. Because of the nature of the active ingredient it is not amenable to the determination of log K_ow according to standard guidelines. For the MMAE part of the active ingredient it would be possible to determine a log K_ow. This has not been done. However, the resulting log K_ow is not to be expected to be above 4.5 as the log octanol-water partitioning coefficient of the building blocks of MMAE Methylvaline, Valine, Dolaisoleucine, Dolaproline, and Norephedrine are each below 4.5 (Platts et al, 2000, Pliska et al, 1981)."

Risk

"The PEC_surfacewater value for brentuximab vedotin is below the action limit of 0.01 μg/L and brentuximab vedotin is not considered a PBT substance due to the size of the molecule. Therefore brentuximab vedotin is not expected to pose a risk to the environment."

Assessment report for Adcetris 2017

Assessment report (Variation assessment report) for Adcetris, 9 November 2017, EMA/753623/2017.

"Brentuximab vedotin is a protein, which is expected to be metabolised in the body and biodegrade in the environment. Thus, according to the "Guideline on the Environmental Risk Assessment of Medicinal Products for Human Use" (EMEA/CHMP/SWP/4447/00), brentuximab vedotin is exempt from the submission of an Environmental Risk Assessment as the product and excipients do not expect to pose a significant risk to the environment. Concerning the antimitotic small molecule MMAE, the PEC_surfacewater calculation was adapted to include the newly added indication. The PEC_surfacewater value is 0.0029 ug/L, which is below the trigger value for a phase II assessment. Overall, it is considered that no significant increase in environmental exposure is anticipated with brentuximab vedotin."

Assessment report for Adcetris 2020

Assessment report (Variation assessment report) for Adcetris, 26 March 2020, EMA/CHMP/213609/2020.

Hazard

Persistence: No data.

Bioaccumulation: "Log K_ow not necessary due to size of molecule. Mw = 153,352 Da."

Toxicity: No data.

"Brentuximab vedotin (SGN-35) is an antibody-drug conjugate (ADC) consisting of three components: 1) the chimeric antibody cAC10, specific for human CD30, 2) the antimicrotubule agent monomethylauristatin E (MMAE), and 3) a protease-cleavable linker that covalently attaches MMAE to cAC10. cAC10 has a structure typical of the human immunoglobulin G1 (IgG1) subclass. Estimated PECsurface water is 3.69 ng L -1. A refined Fpen (4.1×10^-5 ) was used to calculate this PEC, based on a worst-case combined incidence rate of 8.8×10^-4 for the following four indications: Hodgkin’s lymphoma (HL), systemic Anaplastic large cell lymphoma (sALCL), Cutaneous T-cell lymphoma (CTCL) and Peripheral T-cell lymphoma (PTCL). The incidence rates for HL, sALCL and CTCL were published in EMA/COMP public summaries of opinion (PSO) on orphan designation for brentuximab vedotin. The incidence rate for PTCL originates from the current application and corresponds to incidence rates for PTCL as cited in the Orphan Designation PSO's for other active substances (e.g. EMA/694349/2017). Further, a worst-case dose estimation and a full one year prescribed treatment regime were assumed to calculate the cited Fpen. The size of the molecule (molecular weight estimated at 153,352 Da) excludes bioaccumulation. A determination of log K_ow of this substance has not been performed and is not needed. The PBT assessment is therefore concluded. Brentuximab vedotin is not PBT, nor vPvB. The updated data submitted in this application do not lead to a significant increase in environmental exposure further to the use of brentuximab vedotin."

Assessment report for Adcetris 2023

Assessment report (Variation assessment report) for Adcetris, 14 September 2023, EMA/CHMP/440104/2023.

"No new clinical data have been submitted in this application, which was considered acceptable by the CHMP. The most recent ERA included the current three indications in calculations for environmental exposure. As long as the extension of indication variation does not increase the potential population treated beyond these indications, there is no need for a revised ERA."

Fass environmental information

Fass environmental information for Adcetris from Takeda Pharma (downloaded 2024-08-09).

Hazard

Persistence: No data.

Bioaccumulation: No data.

Toxicity: No data.

Risk

Risk of environmental impact of brentuximab vedotin cannot be excluded, due to the lack of environmental toxicity data.