Brentuximab vedotin

Detaljerade information

Allmänt om utredningsrapporter

Sedan 2006 finns krav på att det företag som ansöker om godkännande för försäljning av läkemedel inom EU ska göra en miljöriskbedömning (ERA) för de aktiva läkemedelssubstanserna. Delar av miljödata finns i den publika utredningsrapporten (PAR/EPAR för centralt godkända läkemedel). Miljöhänsyn vägs inte in i nytta-/riskförhållandet för humanläkemedel och miljöaspekter ingår inte heller i efterkontrollsystemet. Det finns således inget krav på företagen att hålla sig informerade om utvecklingen för deras substanser från miljösynpunkt och att därmed uppdatera miljöriskbedömningen vartefter ny information tillkommer.

Brentuximab vedotin har endast genomgått en fas I-studie enligt regulatoriska krav för miljöriskbedömningar (Guideline on the environmental risk assessment of medicinal products for human use, EMEA/CHMP/SWP/4447/00 corr 2). I en fas I-studie ingår data om bioackumulation och man beräknar koncentrationen av brentuximab vedotin i miljön (PEC_ytvatten). Om angivna gränsvärden inte överskrids behöver företaget inte genomföra en fas II-studie som omfattar data om toxicitet och persistens samt beräkning av risk utifrån PEC/PNEC.

Utredningsrapport för Adcetris 2012

Utredningsrapport för Adcetris (brentuximab vedotin), 19 July 2012, EMA/702390/2012.

Fara

Persistens: Inga data.

Bioackumulation: Inga data.

Toxicitet: Inga 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."

Utredningsrapport för Adcetris 2017

Utredningsrapport ("Variation assessment report") för 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."

Utredningsrapport för Adcetris 2020

Utredningsrapport ("Variation assessment report") för Adcetris, 26 March 2020, EMA/CHMP/213609/2020.

Fara

Persistens: Inga data.

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

Toxicitet: Inga 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."

Utredningsrapport för Adcetris 2023

Utredningsrapport ("Variation assessment report") för 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 miljöinformation

Fass miljöinformation för Adcetris från Takeda Pharma (hämtad 2024-08-09).

Fara

Persistens: Inga data.

Bioackumulation: Inga data.

Toxicitet: Inga data.

Risk

Risk för miljöpåverkan av brentuximab vedotin kan inte uteslutas då ekotoxikologiska data saknas.