Detaljerad miljöinformation

Identification and characterisation

Brand name: Kadcyla [1]

Trastuzumab emtansine is an antibody-drug conjugate (ADC) engineered to deliver potent chemotherapy directly to HER2-positive cancer cells, potentially limiting damage to healthy tissues. It combines two anti-cancer properties joined together by a stable linker: the HER2-targeting properties of trastuzumab (the active ingredient in Herceptin) and the chemotherapy agent DM1 (a maytansine derivative). Trastuzumab emtansine is the pharmaceutical active substance in the Roche product Kadcyla. Following endocytosis the conjugate is split through proteolysis, releasing the active moiety MCC-DM1. MCC-DM1 makes up just below 2% of the whole molecular mass of Trastuzumab emtansine: [1]

Substance	CAS number	Mulecular mass
Trastuzumab emtansine (ADC)	1018448-65-1		[1]
Trastuzumab (Antibody)	180288-69-1	98% of ADC	[1]
MCC-DM1 (active moiety)	-	2% of ADC	[1]

Since the ADC Trastuzumab emtansine and the antibody Trastuzumab are readily biodegradable and the active substance MCC-DM1 is not inherently biodegradable, the environmental assessment is made for MCC-DM1. [1]

Predicted Environmental Concentration (PEC)

PEC is calculated according to the formula:

PEC (µg/L) = (A x 1'000'000'000 x (100-R)) / (365 x P x V x D x 100) = 1.37 x 10^-6 x A x (100 - R) = 0.000002 µg/l

(PEC is given for MCC-DM1)

Where:

Trastuzumab emtansine (ADC) 0,73706 kg/y sales data 2023 (Roche internal information)

A Sold quantity = 0.01474 kg/y as: MCC:DM1

R Removal rate = 0% Default [2]

P Population of Sweden = 10 000 000

V Volume of Wastewater = 200 l/day Default [2]

D Factor for Dilution = 10 Default [2]

Predicted No Effect Concentration (PNEC)

Ecotoxicological Studies

Green alga (Desmodesmus subspicatus): [3]

72 h ErC50 (growth rate) >100 mg/l nominal concentration (OECD 201) ADC

72 h ErC50 (yield) = 100 mg/l nominal concentration (OECD 201) ADC

72 h NOEC <100 mg/l nominal concentration (OECD 201) ADC

Water-flea (Daphnia magna): [4]

48 h EC50 >100 mg/l nominal concentration (OECD 202) ADC

48 h NOEC = 100 mg/l nominal concentration (OECD 202) ADC

Guppy (Poecilia reticulata): [5]

96 h LC50 >100 mg/l nominal concentration (OECD 203) ADC

96 h NOEC <100 mg/l nominal concentration (OECD 203) ADC

PNEC Derivation

The PNEC is based on the following considerations:

No ecotoxicity data are available for MCC-DM1. Therefore, a default PNEC was used to estimate the risk of MCC-DM1 for surface water. Default or de minimis PNECs can be adopted from recent retrospective analyses of available aquatic toxicity data with pharmaceuticals. Gunnarsson et al., 2019 [6] reviewed the range of chronic PNECs for 133 compounds and found that for more than 90% these PNECs were >0.01 μg/l and for all hydrophilic (logD_OW <3) substances the PNECs were >0.1 μg/l. When endocrine active substances (EASs) were removed from the analysis more than 90% had PNECs >0.1 μg/l irrespective of hydrophobicity. A similar analysis was carried out on 195 APIs using PNECs from the Swedish Fass.se database of pharmaceuticals (reported in Roos et al., 2012 [7]). These data demonstrate that in more 90% of cases the PNECs reported in Fass.se were ≥0.1 μg/l. In the present case, as a worst-case assumption, a default PNEC of 0.01 µg/l was used.

Default PNEC = 0.01 µg/l MCC-DM1

Environmental Risk Classification (PEC/PNEC Ratio)

PEC Predicted Environmental Concentration = 0,000002 μg/l MCC-DM1 [1]

PNEC Default Predicted No Effect Concentration = 0.01 μg/l MCC-DM1 [1]

Ratio PEC/Default PNEC = 0.0002 MCC-DM1 [1]

A PEC/PNEC = 0.000002/0.01 = 0.0002 for the active moiety MCC-DM1 based on a default PNEC of 0.01 μg/l would justify the phrase 'Use of Trastuzumab emtansine has been considered to result in insignificant environmental risk.' Even with an unrealistically low PNEC of ≥0.00002 μg/l (0.02 ng/l), the ratio PEC/PNEC would be <0.1, indicating an insignificant risk. However, since only a default value was used and no compound specific ecotoxicity tests were performed for the active moiety MCC-DM1, the following phrase applies: 'Risk of environmental impact of Trastuzumab emtansin cannot be excluded, since no ecotoxicity data are available'.

Degradation

Biotic Degradation

Ready biodegradability: [8]
84% after 28 days	BOD/ThOD	(OECD 301 F)	ADC
68% at the end of the 10-d window	BOD/ThOD	(OECD 301 F)	ADC
93% after 28 days	DOC/TOC	(OECD 301 F)	ADC
readily biodegradable
Ready biodegrability: [9]
87% after 14 days	BOD/ThOD	(OECD 301 F)	Antibody
84% at the end of the 10-d window	BOD/ThOD	(OECD 301 F)	Antibody
99% after 28 days	DOC/TOC	(OECD 301 F)	Antibody
readily biodegradable
Inherent biodegradability: [10]
6% after 28 days	BOD/ThOD	(OECD 302 C)	MCC-DM1
79% after 28 days	DOC/TOC	(OECD 302 C)	MCC-DM1
Not inherently biodegradable

The ADC Trastuzumab emtansine and the antibody Trastuzumab (as formulated Herceptin) alone are readily degradable. The active substance MCC-DM1 is not inherently biodegradable. The following phrase applies: 'Trastuzumab emtansine is potentially persistent.'

Bioaccumulation/Adsorption

logDow	= 0.53	pH 5, 25 °C	(OECD 117)	MCC-DM1	[11]
	= 1.16	pH 7, 25 °C	(OECD 117)	MCC-DM1	[11]
	= 0.61	pH 9, 25 °C	(OECD 117)	MCC-DM1	[11]

The environmentally relevant moiety of Trastuzumab emtansine, MCC-DM1, has a low potential for bioaccumulation (logD_OW <4). This justifies the phrase 'Trastuzumab emtansine has low potential for bioaccumulation.'

Excretion/metabolism

Following endocytosis the conjugate is split through proteolysis, releasing the active moiety MCC-DM1 (possibly with small peptide residuals, i.e. lys-MCC-DM1) to block cell division through the tubulin-inhibitory action of the DM1 portion. It is the same MCC-DM1 part, possibly with small peptide residuals (such as lys-MCC-DM1), that is excreted both in mammals and human patients.[1]

References

1. F. Hoffmann-La Roche Ltd (2021): Environmental Risk Assessment Summary for Trastuzumab emtansine. https://www.roche.com/about/sustainability/environment/risk-assessment

2. European Medicines Agency (EMA) (2024): Guideline on the environmental risk assessment of medicinal products for human use. European Medicines Agency, Committee for Medicinal Products for Human Use (CHMP), 15 February 2024, EMA/CHMP/SWP/447/00 Rev. 1

3. BMG Engineering Ltd, on behalf of F. Hoffmann-La Roche Ltd (2010): RO5304020, T-DM1, Fresh water algal growth inhibition tests with Desmodesmus subspicatus, limit test. Study no. A09–01885

4. BMG Engineering Ltd, on behalf of F. Hoffmann-La Roche Ltd (2010): RO5304020, T-DM1, 48-hour acute toxicity to Daphnia magna, limit test. Study no. A09–01886

5. BMG Engineering Ltd, on behalf of F. Hoffmann-La Roche Ltd (2010): RO5304020, T-DM1, 96-hour acute toxicity to Poecilia reticulata (guppy), limit test. Study no. A09–01887

6. Gunnarsson L, Snape JR, Verbruggen B, Owen SF, Kristiansson E, Margiotta-Casaluci L, Österlund T, Hutchinson K, Leverett D, Marks B, Tyler CR (2019): Pharmacology beyond the patient – The environmental risks of human drugs. Environ Int;129:320–332. https://doi.org/10.1016/j.envint.2019.04.075

7. Roos V, Gunnarsson L, Fick J, Larsson DG, Rudén C (2012): Prioritising pharmaceuticals for environmental risk assessment: Towards adequate and feasible first-tier selection. Sci Total Environ;421-422:102–110. https://doi.org/10.1016/j.scitotenv.2012.01.039

8. BMG Engineering Ltd, on behalf of F. Hoffmann-La Roche Ltd (2010): RO5304020, T-DM1, Ready Biodegradability – Evaluation of the Aerobic Biodegradability in an Aqueous Medium: Manometric Respirometry Test. Study no. A09–01884

9. BMG Engineering Ltd, on behalf of F. Hoffmann-La Roche Ltd, Basel, Switzerland (2012): Herceptin. Ready biodegradability – evaluation of the aerobic biodegradability in an aqueous medium: manometric respirometry test. BMG study no. A12-00798

10. BMG Engineering Ltd, on behalf of F. Hoffmann-La Roche Ltd (2012): MCC-DM1, Inherent Biodegradability – Evaluation of the Aerobic Biodegradability in an Aqueous Medium: Modified MITI Test (II). Study no. A11–02096

11. BMG Engineering Ltd, on behalf of F. Hoffmann-La Roche Ltd (2012): MCC-DM1, Determination of the partition coefficient between octanol and water (logPOW) by high performance liquid chromatography (HPLC). Study no. A11–02095