Detaljerad miljöinformation

Identification and characterisation

Brand name: Polivy [1]

Polatuzumab vedotin (Anti-CD79b vcMMAE), an antibody-drug conjugate (ADC), is an anti-human CD79b monoclonal antibody conjugated to monomethyl auristatin E (MMAE). Polatuzumab vedotin is the pharmaceutical active substance in the Roche product Polivy. Polivy is currently approved in combination with bendamustine plus rituximab in the US for the treatment of adults with relapsed or refractory diffuse large B-cell lymphoma, who have received at least two prior therapies, and in Europe for the treatment of adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) who are not candidates for a haematopoietic stem cell transplant. Polatuzumab vedotin is a conjugate of an antibody with small-molecule entities (approximately 3.4–3.5 linker-drug complex vcMMAE units per molecule) of the antibody Polatuzumab, with the latter making up just about 3.17% of the whole molecular mass. The drug MMAE alone makes up 1.73% of the molecular mass of the ADC Polatuzumab vedotin: [1]

Substance	CAS number	Molecular mass
Polatuzumab vedotin (ADC)	1313206-42-6		[1]
Polatuzumab (Antibody)	2279068-37-8	96,8300% of ADC	[1]
linker-drug complex (vcMMAE)	646502-53-6	3,17% of ADC	[1]
Monomethyl auristatin E (MMAE)	474645-27-7	1,73% of ADC	[1]

Since the ADC Polatuzumab vedotin is readily biodegradable and only part of the drug Monomethyl auristatin E (MMAE) remains at the end of the ready biodegradability test with Polatuzumab vedotin, the environmental assessment is made for MMAE. [1, 13, 15]

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) = 0.0000001 µg/l

(PEC is given for MMAE)

Where:

Polatuzumab vedotin (ADC) 0,04212 kg/y, sales data 2022 (Roche internal information)

A Sold quantity = 0.00073 kg/y as: MMAE

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 EyC50 (yield) >100 mg/l nominal concentration (OECD 201) ADC

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

Green alga (Desmodesmus subspicatus): [4]

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

72 h EyC50 (yield) >100 mg/l nominal concentration (OECD 201) Antibody

72 h NOEC = 100 mg/l nominal concentration (OECD 201) Antibody

Green alga (Desmodesmus subspicatus): [5]

72 h ErC50 (growth rate) = 65.8 mg/l initial concentration (OECD 201) vcMMAE

72 h ErC10 (growth rate) = 9.48 mg/l initial concentration (OECD 201) vcMMAE

72 h EyC50 (yield) = 15.6 mg/l initial concentration (OECD 201) vcMMAE

72 h EyC10 (yield) = 3.86 mg/l initial concentration (OECD 201) vcMMAE

72 h NOEC = 4.30 mg/l initial concentration (OECD 201) vcMMAE

vcMMAE was unstable within a short time period. Complete transformation was observed. The transformation product is presumably the drug MMAE. Therefore, evaluation was made based on the initially measured concentration of vcMMAE.

Water-flea (Daphnia magna): [6]

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

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

Water-flea (Daphnia magna): [7]

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

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

Water-flea (Daphnia magna): [8]

48 h EC50 = 24.2 mg/l initial concentration (OECD 202) vcMMAE 1^st test series

48 h NOEC = 6.8 mg/l initial concentration (OECD 202) vcMMAE 1^st test series

vcMMAE was unstable within a short time period. Complete transformation was observed. Later studies confirmed that the transformation product is the drug MMAE. Therefore, evaluation in the 1^st test series was made based on the initially measured concentration of vcMMAE.

Water-flea (Daphnia magna): [8]

48 h EC50 = 4.1 mg/l initial concentration (OECD 202) MMAE 2^st test series

48 h NOEC <3.2 mg/l initial concentration (OECD 202) MMAE 2^st test series

Since the test item vcMMAE was unstable within a short time period, complete transformation was attained before the 2^nd test series was started. Later studies confirmed that the transformation product is the drug MMAE. The evaluation was made based on the initially measured concentration of the transformation product MMAE.

Daphnia magna reproduction test [9]

21 d LOEC = 1.20 mg/l mean measured (OECD 211) MMAE

21 d NOEC = 0.348 mg/l mean measured (OECD 211) MMAE

Since the test item vcMMAE was unstable within a short time period, complete transformation was attained before the test was started. Later studies confirmed that the transformation product is the drug MMAE. The evaluation was made for the transformation product MMAE.

Zebrafish (Danio rerio): [10]

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

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

Zebrafish (Danio rerio): [11]

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

96 h NOEC = 100 mg/l nominal concentration (OECD 203) Antibody

Zebrafish (Danio rerio): [12]

96 h LC50 >47.7 mg/l mean measured (OECD 203) MMAE

96 h NOEC = 47.7 mg/l mean measured (OECD 203) MMAE

The test item vcMMAE was unstable during the course of the study. Complete transformation was observed after 96 h of exposure. Later studies confirmed that the transformation product is the drug MMAE. Therefore, evaluation was made based on the geometric mean measured concentration of the transformation product MMAE.

PNEC Derivation

The PNEC is based on the following data:

PNEC (μg/l) = lowest NOEC/50, where 50 is the assessment factor used. An overall NOEC of 348 μg/l, observed in the Daphnia magna reproduction test with the transformation product MMAE of the test item vcMMAE, has been used for this calculation. [1]

PNEC = 348 μg/l / 50 = 6.96 μg/l

Environmental Risk Classification (PEC/PNEC Ratio)

PEC Predicted Environmental Concentration = 0.0000001 μg/l MMAE [1]

PNEC Predicted No Effect Concentration = 6.96 μg/l MMAE [1]

Ratio PEC/PNEC = 0.00000001 MMAE [1]

PEC/PNEC = 0.0000001/6.96 = 0.00000001 for the drug MMAE which justifies the phrase 'Use of Polatuzumab vedotin has been considered to result in insignificant environmental risk.'

Degradation

Biotic Degradation

Ready biodegradability: [13]

77% after 28 days BOD/ThOD (OECD 301 F) ADC

70% at the end of the 10-d window BOD/ThOD (OECD 301 F) ADC

97% after 28 days DOC/TOC (OECD 301 F) ADC

readily biodegradable

Substance specific HPLC analyses were performed with respect to vcMMAE and the drug MMAE. The analyses showed that all the measurements for vcMMAE were below the limit of quantification (LOQ) of 0.0629 mg/l while the MMAE concentrations steadily increased with time, from 0.192 mg/l after 7 days to 0.274 mg/l after 28 days. Compared to the initial (nominal) concentration of 1.43 mg/l vcMMAE and 0.81 mg/l MMAE, these data suggest that vcMMAE was completely metabolized to MMAE, and that a significant part of the resulting (and initial) MMAE was degraded. [1]

Ready biodegradability: [14]

77% after 28 days BOD/ThOD (OECD 301 F) Antibody

66% at the end of the 10-d window BOD/ThOD (OECD 301 F) Antibody

98% after 28 days DOC/TOC (OECD 301 F) Antibody

readily biodegradable

Inherent biodegradability: ND [15]

13% after 28 days BOD/ThOD (OECD 302 C) vcMMAE

40% after 28 days DOC/TOC (OECD 302 C) vcMMAE

Not inherently biodegradable

The HPLC analyses revealed that vcMMAE dissolved in the test medium during the first day, to reach a maximum of about 19 mg/l, but it never reached its nominal concentration (ca. 30 mg/). After 7 days, vcMMAE was almost entirely primarily degraded and the degradation product - later studies revealed that this is the drug MMAE - reached a maximum concentration of up to about 17 mg/l. Interestingly, the concentration of this degradation product decreased again after day 7, down to about 7 mg/l, while the DOC concentration remained almost constant and the biodegradation based on O₂ consumption hardly increased. This suggests that further transformation products were formed. [1]

The ADC Polatuzumab vedotin and the antibody Polatuzumab alone are readily degradable. The linker-drug complex vcMMAE is not inherently biodegradable. However, complete primary degradation to the drug MMAE occurred and MMAE was further transformed to unknown transformation products to a significant extend. Based on O₂ consumption the following phrase applies: 'Polatuzumab vedotin is potentially persistent.'

Bioaccumulation/Adsorption

logDOW	= 2.45	pH 5, 25 °C	(OECD 117)	vcMMAE	[16]
	= 2.35	pH 7, 25 °C	(OECD 117)	vcMMAE	[16]
	= 2.42	pH 9, 25 °C	(OECD 117)	vcMMAE	[16]
logDOW	= -0.08	pH 5, 25 °C	(OECD 117)	MMAE	[17]
	= 1.17	pH 7, 25 °C	(OECD 117)	MMAE	[17]
	= 1.97	pH 9, 25 °C	(OECD 117)	MMAE	[17]

The environmentally relevant moieties of Polatuzumab vedotin, vcMMAE and MMAE, have a low potential for bioaccumulation (logD_OW <4). This justifies the phrase 'Polatuzumab vedotin has low potential for bioaccumulation.'

Excretion/metabolism

In a preclinical characterization of the distribution, catabolism, and elimination in Sprague Dawley Rats dosed with [3H]-MMAE-Polatuzumab vedotin eight catabolites were detected in the urine and bile samples, of which seven were identified. Unconjugated MMAE was the most abundant catabolite detected. For unconjugated MMAE, based on in vitro, preclinical, and clinical data, the elimination of was assumed to be predominantly through the CYP3A4/5-mediated metabolic pathway and biliary/faecal excretion. Limited renal excretion (<10%) of MMAE has been reported. [1]

References

1. F. Hoffmann-La Roche Ltd (2021): Environmental Risk Assessment Summary for Polatuzumab vedotin. https://www.roche.com/sustainability/environment/environmental-risk-assessment-downloads.htm

2. European Medicines Agency (EMA) (2006/2015): Guideline on the environmental risk assessment of medicinal products for human use. European Medicines Agency, Committee for Medicinal Products for Human Use (CHMP), 01 June 2006, EMA/CHMP/SWP/447/00 corr 2

3. Arcadis Schweiz Ltd, on behalf of F. Hoffmann-La Roche Ltd, Basel, Switzerland (2018): DCDS4501S (aCD79b vcMMAE) Drug Product (Ph III). Fresh water algal growth inhibition test with Desmodesmus subspicatus; limit test with 100 mg Polatuzumab vedotin/L. ACH study no. A18-00488

4. Arcadis Schweiz Ltd, on behalf of F. Hoffmann-La Roche Ltd, Basel, Switzerland (2018): Polatuzumab AB, MCDS4409A Bulk Intermediate. Fresh water algal growth inhibition test with Desmodesmus subspicatus; limit test with 100 mg Polatuzumab Ab/L. ACH study no. A18-00484

5. Arcadis Schweiz Ltd, on behalf of F. Hoffmann-La Roche Ltd, Basel, Switzerland (2016): SGD-1006 (vcMMAE). Fresh water algal growth inhibition test with Desmodesmus subspicatus. ACH study no. A15-00558

6. Arcadis Schweiz Ltd, on behalf of F. Hoffmann-La Roche Ltd, Basel, Switzerland (2018): DCDS4501S (aCD79b vcMMAE) Drug Product (Ph III). 48-Hour acute toxicity to Daphnia magna; limit test with 100 mg Polatuzumab vedotin/L. ACH study no. A18-00489

7. Arcadis Schweiz Ltd, on behalf of F. Hoffmann-La Roche Ltd, Basel, Switzerland (2018): Polatuzumab AB, MCDS4409A Bulk Intermediate 48-Hour acute toxicity to Daphnia magna; limit test with 100 mg Polatuzumab Ab/L. ACH study no. A18-00485

8. Arcadis Schweiz Ltd, on behalf of F. Hoffmann-La Roche Ltd, Basel, Switzerland (2016): SGD-1006 (vcMMAE). 48-Hour acute toxicity to Daphnia magna. ACH study no. A15-00559

9. Arcadis Schweiz Ltd, on behalf of F. Hoffmann-La Roche Ltd, Basel, Switzerland (2016): SGD-1006 (vcMMAE). Daphnia magna reproduction test ACH study no. A15-00561

10. Arcadis Schweiz Ltd, on behalf of F. Hoffmann-La Roche Ltd, Basel, Switzerland (2018): DCDS4501S (aCD79b vcMMAE) Drug Product (Ph III). 96-Hour acute toxicity to Danio rerio (Zebrafish); limit test with 100 mg Polatuzumab vedotin/L. ACH study no. A18-00490

11. Arcadis Schweiz Ltd, on behalf of F. Hoffmann-La Roche Ltd, Basel, Switzerland (2018): Polatuzumab AB, MCDS4409A Bulk Intermediate. 96-Hour acute toxicity to Danio rerio (Zebrafish); limit test with 100 mg Polatuzumab Ab/L. ACH study no. A18-00486

12. Arcadis Schweiz Ltd, on behalf of F. Hoffmann-La Roche Ltd, Basel, Switzerland (2016): SGD-1006 (vcMMAE). 96-Hour acute toxicity to Danio rerio (Zebrafish). ACH study no. A15-00560

13. Arcadis Schweiz Ltd, on behalf of F. Hoffmann-La Roche Ltd, Basel, Switzerland (2018): DCDS4501S (aCD79b vcMMAE) Drug Product (Ph III). Ready biodegradability – evaluation of the aerobic biodegradability in an aqueous medium: manometric respirometry test. ACH study no. A18-00491

14. Arcadis Schweiz Ltd, on behalf of F. Hoffmann-La Roche Ltd, Basel, Switzerland (2018): Polatuzumab AB, MCDS4409A Bulk Intermediate. Ready biodegradability – evaluation of the aerobic biodegradability in an aqueous medium: manometric respirometry test. ACH study no. A18-00487

15. Arcadis Schweiz Ltd, on behalf of F. Hoffmann-La Roche Ltd, Basel, Switzerland (2016): SGD-1006 (vcMMAE). Inherent biodegradability – evaluation of the aerobic biodegradability in an aqueous medium: modified MITI test (II). ACH study no. A15-00562

16. Arcadis Schweiz Ltd, on behalf of F. Hoffmann-La Roche Ltd, Basel, Switzerland (2016): SGD-1006 (vcMMAE). Determination of the partition coefficient between octanol and water by high performance liquid chromatography (HPLC). ACH study no. A15-00557

17. Arcadis Schweiz Ltd, on behalf of F. Hoffmann-La Roche Ltd, Basel, Switzerland (2018): MMAE. Determination of the partition coefficient between octanol and water by high performance liquid chromatography (HPLC). ACH study no. A18-00492