Detaljerad miljöinformation

Environmental Risk Classification

Predicted Environmental Concentration (PEC)

PEC is calculated according to the following formula:

PEC (μg/L) = (A*10⁹*(100-R)/(365*P*V*D*100) = 1.37*10^-6*A(100-R)

PEC = 7.54 x10^-5 μg/L

Where:

A = 0.55 kg (total sold amount API in Sweden year 2022, data from IQVIA). Reduction of A may be justified based on metabolism data.

R = 0% removal rate (conservatively, it has been assumed there is no loss by adsorption to sludge particles, by volatilization, hydrolysis or biodegradation)

P = number of inhabitants in Sweden = 10 *10⁶

V (L/day) = volume of wastewater per capita and day = 200 (ECHA default) (Reference 1)

D = factor for dilution of waste water by surface water flow = 10 (ECHA default) (Reference 1)

Predicted No Effect Concentration (PNEC)

Ecotoxicological studies

Green Algae:

No data

Water flea:

Acute toxicity

No data

Water flea:

Chronic toxicity

No Data

Fish:

Acute toxicity

No data

Chronic toxicity

No Data

Other ecotoxicity data:

No data

PNEC cannot be calculated because data is not available for all three (algae, crustacean and fish) of the short-term toxicity endpoints.

Environmental risk classification (PEC/PNEC ratio)

According to the European Medicines Agency guideline on environmental risk assessment of medicinal products (EMA/CHMP/SWP/4447/00), use of ambrisentan is unlikely to represent a risk for the environment, because the predicted environmental concentration (PEC) is below the action limit 0.01 μg/L (Reference 2).

Degradation

Biotic degradation

Ready degradability:

No data

Inherent degradability:

No Data

Abiotic degradation

Hydrolysis:

No data

Photolysis:

No data

Justification of chosen degradation phrase:

There are no degradation available for ambrisentan. The phrase “The potential for persistence of ambrisentan cannot be excluded, due to lack of data” is thus chosen.

Bioaccumulation

Partitioning coefficient:

Log Dow_calculated = 0.56 @ pH 7 (Reference 4)

Justification of chosen bioaccumulation phrase:

Since log Dow < 4, the substance has low potential for bioaccumulation.

Excretion (metabolism)

Ambrisentan is glucuronidated via several UGT isoenzymes (UGT1A9S, UGT2B7S and UGT1A3S) to form ambrisentan glucuronide (13%). Ambrisentan also undergoes oxidative metabolism mainly by CYP3A4 and to a lesser extent by CYP3A5 and CYP2C19 to form 4-hydroxymethyl ambrisentan (21%) which is further glucuronidated to 4-hydroxymethyl ambrisentan glucuronide (5%). The binding affinity of 4-hydroxymethyl ambrisentan for the human endothelin receptor is 65-fold less than ambrisentan. Therefore at concentrations observed in the plasma (approximately 4% relative to parent ambrisentan), 4-hydroxymethyl ambrisentan is not expected to contribute to pharmacological activity of ambrisentan.

Ambrisentan and its metabolites are eliminated primarily in the bile following hepatic and/or extra-hepatic metabolism. Approximately 22% of the administered dose is recovered in the urine following oral administration with 3.3% being unchanged ambrisentan. Plasma elimination half-life in humans ranges from 13.6 to 16.5 hours (Reference 3).

References

1. ECHA, European Chemicals Agency. 2008 Guidance on information requirements and chemical safety assessment.

2. FASS.se, Environmental Classification of Pharmaceuticals. 2012 (v 3.0) Guidance for pharmaceutical companies.

3. Pharmacokinetic properties: Metabolism and Elimination. Summary of Product Characteristics Volibis (Ambrisentan). GlaxoSmithKline plc, October 2014.

4. Chemaxon /LogD. December 2014. Instant J Chem, ChemAxon Ltd.