Detaljerad miljöinformation

Enhertu

T-DXd (Trastuzumab deruxtecan)

T-DXd is an Antibody Drug Conjugate (ADC) composed of an anti-HER2 mAb covalently conjugated to a drug-linker, deruxtecan.  The drug-linker is composed of a cleavable maleimide tetrapeptide and the released drug, DXd.  The schematic structures of T-DXd, deruxtecan, DXd, and mAb are provided above. The three components of T-DXd, mAb, linker, and DXd, will be examined individually within this assessment. The three components are designed to dissociate from one another once bound to the HER2 positive target cell in patients and therefore they will be excreted separately and can be treated as separate molecules within the environmental risk assessment.

Schematic structures of T-DXd, Deruxtecan, DXd, and mAb

Name(s)	Structure	Molecular Weight (Da)
T-DXd (Trastuzumab deruxtecan)		~158000
Deruxtecan		1034.05
DXd		493.484
mAb	Humanized anti-HER2 monoclonal immunoglobulin G1	~150000

The assessment which follows addresses the risk from the drug component (non-protein-moiety) termed DXd in this assessment. The risks from the protien based moieties have been addressed at the end of this assessment

Risk Phrase Summary

	English	Swedish
Environmental risk:	The environmental risk impact of trastuzumab deruxtecan cannot be ruled out as there is insufficient ecotoxicological data.	Risk för miljöpåverkan av trastuzumab deruxtekan kan inte uteslutas då det inte finns tillräckliga ekotoxikologiska data..
Degradation:	The potential for persistence of DXd cannot be excluded, due to lack of data.	Det kan inte uteslutas att DXd är persistent, då data saknas
Bioaccumulation:	“DXd has low potential for bioaccumulation”	DXd har låg potential att bioackumuleras

Miljörisk

Drug (DXd)

English: According to the European Medicines Agency guideline on environmental risk assessment of medicinal products (Ref. 1; EMA/CHMP/SWP/4447/00), use of DXd 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.

Swedish: Enligt den europeiska läkemedelsmyndigheten EMA:s riktlinjer för miljöriskbedömning av läkemedelssubstanser (Ref. 1; EMA/CHMP/SWP/4447/00), bedömdes det vid registreringstillfället vara osannolikt att användningen av DXd kommer att medföra en miljörisk, då det förväntas att användningen ger en koncentration i miljön (PEC) som bli lägre än tröskelvärdet 0,01 µg/L.

However, some environmental data has been generated on the active drug (DXd) and as such an assessment has been presented.

Detaljerad miljöinformation

PEC = 2.1 x 10^-8 µg/L

PNEC = 0.23 µg/L

PEC/PNEC = 9.1 x 10^-8

Environmental Risk Classification

Predicted Environmental Concentration (PEC)

On average, the target number of drug-linker (deruxtecan) to 1 antibody molecule is 8. The molecular weight of T-DXd is approximately 158,000 Da. On average 8 molecules of the active drug (DXd at 493.484 Da) are present on each molecule (8 × 493.484 = 3947.872 Da), thus DXd represents approximately 2.5% of the total dose of T-DXd (3947.872 ÷ 158 000 = 2.5%). Because only the active component of T-DXd is relevant for environmental risk assessment, the sold quantity of API is multiplied by 2.5% to obtain the total amount of DXd (or active drug) relevant for PEC calculation.

The PEC is based on the following data:

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

PEC (µg/L) = 1.37*10^-6*A*(100-R) 

Where;

A (kg/year) = 2.5% x 0.0061 kg = 0.0001525 kg total sold amount API (DXd) in Sweden year 2021, data from IQVIA.

R (%) = removal rate (due to loss by adsorption to sludge particles, by volatilization, hydrolysis or biodegradation). R = 0, this provides a worst-case surface water exposure estimate.

P = number of inhabitants in Sweden =10*10⁶

V (L/day) = volume of wastewater per capita and day = 200 L/day (Ref 7)

D = factor for dilution of waste water by surface water flow = 10 (Ref 7)

(Note: The factor 10⁹ converts the quantity used from kg to μg)

PEC = 1.37 * 10^-6 *0.0001525*(100-0) = 2.1 x 10^-8 µg/L

Metabolism and excretion

Following administration the three components are designed to dissociate from one another once bound to the HER2 positive target cell in patients and therefore they will be excreted separately and can be treated as separate molecules within the environmental risk assessment.

Ecotoxicity Data

Endpoint	Species	Common Name	Method	Time	Result	Ref
ErC10 – Based on Growth Rate	Pseudo-kirchneriella subcapitata	Green Algae	OECD 201	72 h	0.0807 mg/L	3
NOEC – Based on Growth Rate					0.023 mg/L
NOEC - Based on Growth Rate	Anabaena flos-aquae	Cyanobacteria	OECD 201	72 h	2.58 mg/L	4
NOEC – Reproduction	Daphnia magna	Giant Water Flea	OECD 211	21 d	0.0342 mg/L	5
EC10 - Reproduction					0.0607 mg/L
NOEC	N/A	Activated sludge	OECD 209	3h	1000 mg/L	6

NOEC                No Observed Effect Concentration 

NOEC                No Observed Effect Concentration

LOEC                 Lowest Observed Effect Concentration 

EC₁₀                   the concentration of the test substance that results in a 10% effect 

Environmental Fate Data

No Data

Degradation

No Data

The potential for persistence of DXd cannot be excluded, due to lack of data.

In Swedish: Det kan inte uteslutas att DXd är persistent, då data saknas

Bioaccumulation 

The octanol/water partition coefficient of DXd was determined as a function of pH, across the environmentally relevant pH range.  

Since the measured Log Dow values were < 4; DXd is considered to have a low potential to bioaccumulate and the phrase “DXd has low potential for bioaccumulation” is assigned. 

In Swedish: DXd har låg potential att bioackumuleras.

Physical Chemistry Data

Study Type	Method	Result	Ref
Water solubility	OECD 105	7.52 mg/L	7
Octanol – water partition coefficient	OECD 107	pH 5 log Dow = 1.92  pH 7 log Dow = 1.80  pH 9 log Dow = 1.28	8

Miljörisk

The assessment which follows addresses the risk from the protein-moieties in the form of the monoclonal antibody and tetrapeptide linker.

Monoclonal antibody (mAb) and tetrapeptide linker (deruxtecan)

Användning av peptider bedöms inte medföra någon miljöpåverkan.

The use of amino peptides has been considered to result in insignificant environmental impact.

The monoclonal antibody and the tetrapeptide linker molecules are a monoclonal antibody and peptide respectively and as such is considered to result in insignificant environmental impact. According to the EU EMA guideline for Environmental Risk Assessment of pharmaceuticals vitamins, electrolytes, amino acids, peptides, proteins, carbohydrates and lipids are exempted because they are unlikely to result in significant risk to the environment (Ref. 1).

Therefore the statement: “The use of amino peptides has been considered to result in insignificant environmental impact. “

In Swedish: ”Användning av peptider bedöms inte medföra någon miljöpåverkan.”

References

1. 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.

2. ECHA, European Chemicals Agency. 2008 Guidance on information requirements and chemical safety assessment. http://guidance.echa.europa.eu/docs/guidance_document/information_requirements_en.htm

3. MAAA-1181d: Determination of toxicity to the green alga Pseudokirchneriella subcapitata. Study/Report Number: 1075.00208. Scymaris Ltd., Brixham Laboratory, Freshwater Quarry, Brixham, Devon, TQ5 9BA, UK. 11 May 2021

4. MAAA-1181d: Determination of toxicity to the blue green alga Anabaena flos-aquae. Study/Report Number: 1075.00209. Scymaris Ltd., Brixham Laboratory, Freshwater Quarry, Brixham, Devon, TQ5 9BA, UK. 29 September 2021

5. MAAA-1181d: Determination of effects on reproduction to Daphnia magna. Study/Report Number: 1075.00210. Scymaris Ltd., Brixham Laboratory, Freshwater Quarry, Brixham, Devon, TQ5 9BA, UK. 12 May 2021

6. MAAA-1181d: Activated Sludge, Respiration Inhibition Test. Study/Report Number: 1075.00211. Scymaris Ltd., Brixham Laboratory, Freshwater Quarry, Brixham, Devon, TQ5 9BA, UK. 18 January 2021

7. MAAA-1181d: Water solubility. Study/Report Number: 1075.00203. Scymaris Ltd., Brixham Laboratory, Freshwater Quarry, Brixham, Devon, TQ5 9BA, UK. 21 April 2020

8. MAAA-1181d: Partition coefficient (n-octanol/water): Shake flask method. Study/Report Number: 1075.00204. Scymaris Ltd., Brixham Laboratory, Freshwater Quarry, Brixham, Devon, TQ5 9BA, UK. 21 April 2020