Linaklotid

Detaljerad 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.

Utredningsrapport för Constella (linaklotid), Allergan Pharmaceuticals International Limited, 20 september 2012, EMA/CHMP/60979/2012

"The active ingredient linaclotide is a peptide. A general exemption from an environmental risk assessment is granted for peptides in guideline (EMEA/CHMP/SWP/4447/00). This exemption is based on the assumptions that peptides are readily biodegradable, can only be administered in a parenteral way, are not excreted in an intact form and do not reach the environment. These assumptions are not true for linaclotide. Linaclotide is a member of the guanylin peptide family, which includes the natural hormones uanylin and uroguanylin as well as the bacterial heat stable enterotoxin, STa. Like STa, linaclotide is stable across a broad pH range including low pH found in the stomach. Due to its exceptional stability (compared to other peptides), linaclotide may be administered orally. In the human intestinal tract the 14th amino acid, Tyrosin, is cleaved resulting in an equally bioactive metabolite MM 419447. The active ingredient and its active metabolite are excreted to up to 6 % and might reach the environment. Therefore no general exemption can be granted from an environmental risk assessment for linaclotide. The environmental risk assessment at Phase I leads to a PEC_{surface water} below 0.01 µg/L. According to EMEA/CHMP/SWP/4447/00 information on the octanol-water partitioning coefficient for the active ingredient is required in Phase I. However, the octanol/water partition coefficient that is normally used in Phase I to screen for potentially bioaccumulative substances is not a good predictor for this property for macromolecular compounds of the size of linaclotide. The applicant states that considering all available information (low Log K_ow, high solubility and low permeability into Caco-2 cells) suggest that bioaccumulation of linaclotide should be considered very unlikely. This was accepted by the CHMP."

Fara

Persistens: Data saknas.

Bioackumulation: Log D_ow (pH 7,4) är sannolikt under -2. "A PBT assessment has not been conducted. The available information from the PBT screening step (low log D_ow, high solubility and low permeability into Caco-2 cells in virtro) suggests that bioaccumulation of linaclotide should be considered very unlikely." 

Toxicitet: Data saknas.

Risk

PEC_surfacewater, default = 0,00145 mikrog/L. "A Phase II assessment has not been conducted as PEC_surfacewater is below the action limit of 10 ng/L."