Osimertinib Mesylate
Environmental Risk Assessment Data Osimertinib
Osimertinib is used for treatment of adult patients with locally advanced or metastatic epidermal growth factor receptor (EGFR) T790M mutation-positive non-small-cell lung cancer (NSCLC). Osimertinib, is a tyrosine kinase inhibitor. It blocks the activity of EGFR, which normally controls growth and division of cells. In lung cancer cells, EGFR is often overactive, causing uncontrolled division of cancer cells. By blocking EGFR, osimertinib helps to reduce the growth and spread of the cancer. Unlike most other tyrosine kinase inhibitors, Tagrisso is active against cancer cells with the T790M mutation in the EGFR gene.
Osimertinib is the active pharmaceutical ingredient used in the AstraZeneca product, Tagrisso.
Osimertinib is adsorbed and extensively metabolised in patients. Following oral administration, the does is largely excreted in faeces (~ 68%) and to a lesser extent urine (~14%). Unchanged osimertinib accounted for approximately 2% of the total elimination with 0.8% in urine and 1.2% in faeces.
Osimertinib cannot be classified as readily biodegradable, but is expected to be significantly removed, via adsorption, during sewage treatment. Osimertnib is unlikely to persist in surface waters and is not predicted to bioaccumulate in aquatic organisms.
The Predicted Environmental Concentration (PEC) / Predicted No Effect Concentration (PNEC) ratio is 1.9 x 10-2, which means use of osimertinib is predicted to present an insignificant risk to the environment.
Predicted Environmental Concentration (PEC) Since osimertinib is a recently launched AstraZeneca drug substance, the PEC is based on the calculation in the EMA guideline (Ref. 1).
DOSEaiFpen PEC 10200 Where: DOSEai = maximum daily dose consumed per inhabitant = 80 mg/inhabitant/day Fpen = percentage of market penetration = 0.0000361 V (L/day) = volume of wastewater per capita and day = 200 (Ref 1) D = factor for dilution of waste water by surface water flow = 10 (Ref 1)
800.000036 PEC 10200
PEC = 0.0000014 mg/L or 0.0014 µg/L
(Note: Whilst osimertinib is metabolised in the body, little is known about the ecotoxicity of the metabolites. Hence, as a worst case, for this calculation, it is assumed that 100% of excreted metabolites have the same ecotoxicity as parent osimertinib).
1 The Fpen represents the fraction of a population receiving the drug substance during a given time. This is calculated using the disease prevalence data. The highest single year prevalence of lung cancer is reported for Hungary, 50 per 100,000 total population (http://globocan.iarc.fr accessed 07.08.2017). Approximately 80% (Ref 2) to 89% (Ref 3 & 4) of these are expected to be NSCLC, with approximately 7% to 13% (Ref 2, 5-8) of those having the EGFR mutation. Of the patients with EGFR m up to 62% (maximum) develop the secondary T790 mutation (Ref 8 & 9). Therefore, the Fpen is calculated; (50/100000) × 0.89 × 0.13 × 0.62 = 0.000036 Predicted No Effect Concentration (PNEC) Long-term tests have been undertaken for species from three trophic levels, based on internationally accepted guidelines. Therefore, the PNEC is based on the lowest No Observed Effect Concentration (NOEC) 0.00075 mg/L (equivalent to 0.75 µg/L) which was reported for fathead minnows in the fish early life-stage test, and an assessment factor of 10 is applied, in accordance with EMA guidance (Ref 1).
PNEC = 0.75 µg/L /10 = 0.075 µg/L
PEC/PNEC PEC = 0.0014 µg/L PNEC = 0.075 µg/L
PEC/PNEC = 1.9 x 10-2
The PEC/PNEC ratio of 1.9 x 10-2 corresponds to the phrase ‘Use of the substance has been considered to result in insignificant environmental risk’ in the www.fass.se scheme (Ref 10).
Environmental Fate Summary Osimertinib is fairly water soluble and has been shown to strongly adsorb to sewage sludge, sediments and soils. As such it is expected to be significantly removed during sewage treatment and is unlikely to remain present in surface waters. The octanol-water partition coefficients, measured across the environmentally relevant pH range, are low and osimertinib is not predicted to bioaccumulate in aquatic organisms.
Aquatic Toxicity Data for Osimertinib Mesylate Study Type Method Result Ref Activated sludge, respiration OECD209 3 hour NOEC = 31.25 mg/L 11 inhibition test 3 hour EC50 ≥ 320 mg/L Toxicity to green algae, OECD201 72 hour NOEC (growth rate) =0.014 mg/L 12 Pseudokirchinella subcapitata, 72 hour LOEC (growth rate) =0.076 mg/L growth inhibition test4 72 hour EC50 (growth rate) = 0.23 mg/L
72 hour NOEC (biomass) = 0.014 mg/L 72 hour LOEC (biomass) = 0.076 mg/L 72 hour EC50 (biomass) = 0.047 mg/L Acute toxicity to Daphnia magna OECD202 48 hour EC50 (immobility) = 1.5 mg/L 13 Chronic toxicity to Daphnia OECD210 21 day LOEC (survival, reproduction and 14 magna growth) = 0.10 mg/L 21 day NOEC (survival, reproduction and growth) = 0.026 mg/L Fish Early-Life Stage Toxicity with OECD211 32 day LOEC (hatch, survival, growth) 15 Pimephales promelas, = 0.0027 mg/L 32 day NOEC (hatch, survival, growth) = 0.00075 mg/L Study Type Method Result Ref Toxicity to Chironomus riparius OECD218 28 day NOEC (total emergence, 16 development rate, sex ratio) = 79 mg/kg dry weight 28 day LOEC (total emergence, development rate, sex ratio > 79 mg/kg dry weight NOEC No Observed Effect Concentration LOEC Lowest Observed Effect Concentration EC50 the concentration of the test substance that results in a 50% effect LC50 the concentration of the test substance that results in a 50% mortality
Environmental Fate Data for Osimertinib Study Type Method Result Ref Biodegradation in OECD 314B Degradation followed first-order kinetics; 17 activated sludge Biotic DT50 = 2.8 days Abiotic DT50 = 1.1 days There was extensive association of the radioactivity with the sludge solids with no 14 significant formation of CO2 One degradation product, present in both biotic and abiotic samples, accounted for greater than 10% of the applied radioactivity Aerobic transformation in OECD308 Rapid dissipation from the water phase, 18 aquatic sediment systems aqueous phase dissipation half-life < 1 day in both test systems. The dissipation half-lives for the total system in the high and low organic carbon sediments were 1 and 3 days, respectively. DT50 in the sediment phase, first-order kinetics, was in the range 9-16 days Adsorption coefficients to OECD106 Soils: 19 soils, sediments and active Empingham(pH 7.6, 3.6% OC) sewage sludge Kd = 3702 L/Kg; Koc = 102830 L/Kg Warsop(pH 4.1, 0.7% OC) Kd = 5384 L/Kg; Koc = 769189 L/Kg
Sediments: Calwich Abbey(pH 7.1, 4.9% OC) Kd = 9354 L/Kg; Koc = 190886 L/Kg Swiss Lake(pH 5.4, 0.6% OC) Kd = 6219 L/Kg; Koc =1036439 L/Kg
Sewage sludge: Burley Menston(35.8% OC) Kd = 4784 L/Kg; Koc = 16663 L/Kg DT50 Degradation half-life OC Organic Carbon Kd Distribution coefficient for adsorption Koc Organic carbon normalized adsorption coefficient Physical Chemistry Data for Osimertinib Study Type Method Result Ref Water solubility Not-stated 3.1 mg/mL 20 Disassociation constant Not-stated pKa = 9.5 (aliphatic amine) 20 pKa = 4.4 (aniline) Octanol – water partition OECD 107 pH 4 log Dow = 1.77 21 coefficient pH 7 log Dow = 2.45 pH 9 log Dow = 2.69
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