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Erivedge

Roche

Kapsel, hård 150 mg
(Rosafärgad ogenomskinlig underdel märkt ”150 mg” och grå ogenomskinlig överdel märkt ”VISMO” med svart bläck. Kapselstorleken är ‘storlek 1’ (dimensioner 19,0 x 6,6 mm).)

Antineoplastiska medel

Aktiv substans:
ATC-kod: L01XX43
Utbytbarhet: Ej utbytbar
Läkemedel från Roche omfattas av Läkemedelsförsäkringen.
  • Vad är miljöinformation?

Miljöinformation

Miljöpåverkan

Vismodegib

Miljörisk: Användning av vismodegib har bedömts medföra försumbar risk för miljöpåverkan.
Nedbrytning: Vismodegib är potentiellt persistent.
Bioackumulering: Vismodegib har låg potential att bioackumuleras.


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Detaljerad miljöinformation

Identification and characterisation

Chemical name: Vismodegib

CAS number: 879085-55-9 [1]

Molecular weight: 421.31 [1]

Remark: -

Brand name: Erivedge [1]


Physico-chemical properties

Aqueous solubility: 0.879 mg/l (20 °C) (OECD 105) [1]

Dissociation constant, pKa: 3.4–3.5 (base) [1]

Melting point: 186–188 °C (OECD 102) [1]

Vapour pressure: ND

Boiling point: ND

KH: 8.87*E–15 atm*m3/mol QSAR


QSAR = QSAR-modelled (EPISuite, SPARC, ACD Solaris)


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) = 1.5 x 10-6 x A x (100 - R) = 0.00016 μg/L


Where:

A Sold quantity = 1.0794 kg/y (total sold amount API in Sweden year 2017, data from IQVIA)

R Removal rate = 0 % Default [2]

P Population of Sweden = 9000000

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 (Raphidocelis subcapitata): [3]

72 h ErC50 (growth rate) = 118 μg/l (OECD 201)

72 h ErC10 (growth rate) = 92 μg/l (OECD 201)

72 h EyC50 (yield) = 99 μg/l (OECD 201)

72 h EyC10 (yield) = 81 μg/l (OECD 201)

72 h NOEC (overall) = 69 μg/l (OECD 201)


Water-flea (Daphnia magna): [4]

21 d NOEC (reproduction) = 1500 μg/l (OECD 211)


Zebra fish (Danio rerio): [5]

35 d NOEC (overall NOEC) = 1600 μg/l (OECD 210)


Micro-organisms (activated sludge):

3 h NOEC = 1000 mg/l (OECD 209) [6]

28 d NOEC (toxicity control) = 54 mg/l (OECD 301 F) [7]


PNEC Derivation

The PNEC is based on the following data:

PNEC (mg/l) = lowest chronic NOEC/10, where 10 is the assessment factor used. A NOEC of 69 μg/l for Algae has been used for this calculation.

PNEC = 69 / 10 = 6.9 μg/l


Environmental Risk Classification (PEC/PNEC Ratio)

PEC Predicted Environmental Concentration = 0.00016 μg/L

PNEC Predicted No Effect Concentration = 6.9 μg/L

Ratio PEC/PNEC = 0.00002


PEC/PNEC =0.00016/6.9 = 0.00002 for Vismodegib which justifies the phrase 'Use of Vismodegib has been considered to result in insignificant environmental risk.'


Degradation


Biotic Degradation

Ready biodegradability: [7]

0% after 28 days of incubation BOD/ThOD (OECD 301 F)


Inherent biodegradability: ND


Other degradation information: [8]

DT50 (water) = 3.3–3.7 d (OECD 308)

DT50 (sediment) >1 y (OECD 308)

DT50 (total system) >1 y (OECD 308)


Abiotic Degradation

Photodegradation: ND

Hydrolysis: ND


Vismodegib is not readily biodegradable; it is also not degradable in water/sediment systems. This justifies the phrase 'Vismodegib is potentially persistent.'


Bioaccumulation/Adsorption


logPOW = 1.59 (pH 7, non-dissociated state) (OECD 117) [9]

KOC (soils) = 2129–5001 l/kg (OECD 106) [10]

KOC (sludges) = 684–895 l/kg (OECD 106) [10]

BCF = 54 l/kg QSAR


Vismodegib has low potential for bioaccumulation since the log POW is <4..


Excretion/metabolism


The metabolism of vismodegib was investigated in both in vitro and in vivo investigations. The major metabolic pathways involved oxidations of the 4-chloro-3 (pyridine-2-yl)-phenyl moiety followed by sequential glucuronidation or sulfation. In mass balance studies in rat and dog, drug derived radioactivity was recovered largely in feces followed by bile. [11]


References

1. F. Hoffmann-La Roche Ltd. 2019. Safety Data Sheet for Vismodegib, 01.04.2019; https://www.roche.com/sustainability/what_we_do/for_communities_and_environment/environment/safety_data_sheetsrow. htm.

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. Harlan Laboratories, on behalf of F. Hoffmann-La Roche Ltd, Basel, Switzerland (2011). RO5450815-000: Toxicity to Pseudokirchneriella subcapitata in a 72-Hour Algal Growth Inhibition Test. Harlan study no. D09861.

4. Harlan Laboratories, on behalf of F. Hoffmann-La Roche Ltd, Basel, Switzerland (2011). RO5450815-000: Effect on Survival and Reproduction of Daphnia magna in a Semi-Static Test over Three Weeks. Harlan study no. D096631.

5. Harlan Laboratories, on behalf of F. Hoffmann-La Roche Ltd, Basel, Switzerland (2011). RO5450815-000: Toxic Effects to Zebrafish (Brachydanio rerio ) in an Early-Life Stage Toxicity Test. Harlan study no. C96642.

6. Harlan Laboratories, on behalf of F. Hoffmann-La Roche Ltd, Basel, Switzerland (2010). RO5450815-000: Toxicity to Activated Sludge in a Respiration Inhibition Test. Harlan study no. C96653.

7. BMG Engineering Ltd, on behalf of F. Hoffmann-La Roche Ltd, Basel, Switzerland (2010). PAS-RO5450815-000. Ready biodegradability – Evaluation of the aerobic biodegradability in an aqueous medium: Manometric Respirometry Test. BMG study no. A09–01583.

8. Harlan Laboratories, on behalf of F. Hoffmann-La Roche Ltd, Basel, Switzerland (2011). [14C]-RO5450815-000: Route and Rate of Degradation in Aerobic Aquatic Sediment Systems. Harlan study no. C96620.

9. BMG Engineering Ltd, on behalf of F. Hoffmann-La Roche Ltd, Basel, Switzerland (2010). PAS-RO5450815-000. Determination of the partition coefficient between octanol and water (logPow) by high-performance liquid chromatography (HPLC). BMG study no. A09–01587.

10. Harlan Laboratories, on behalf of F. Hoffmann-La Roche Ltd, Basel, Switzerland (2011). [14C]-RO5450815-000: Adsorption/Desorption on Three Soils and Two Sludges. Harlan study no. C96618.

11. European Medicines Agency (EMA). Committee for Medicinal Products for Human Use (CHMP). Assessment report for Erivedge. EMA/297688/2013, 25 April 2013.