Detaljerad miljöinformation

Environmental Risk Classification

Predicted Environmental Concentration (PEC)

The 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 = 1.37 x 10-6 x 10 x (100-0)

PEC = 0.00137 μg/L

Where:

A = 10 kg (Forecasted sales data of less than 10 kg five years after launch.)

R = 0 % removal rate as a concervative estimate.

P = number of inhabitants in Sweden = 10 *10⁶

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

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

Excretion (metabolism) 

Mavacamten is extensively metabolized, primarily through CYP2C19 (74%), CYP3A4 (18%) and CYP2C9 (~8%)².  Following a single 25 mg dose of radiolabeled mavacamten, 7% of the dose was recovered in feces (1% as unchanged mavacamten) and 85% in urine (3% as unchanged mavacamten). No removal is used as a worst-case scenario for the PEC calculation above.

Predicted No Effect Concentration (PNEC)

Ecotoxicological studies

Activiated sludge (OECD 209)³

EC₅₀ (3-h respiration inhibition) > 1000 mg/L (highest dose tested)

EC₁₀ (3-h respiration inhibition) = 62.7 mg/L

Algae (Raphidocelis subcapitata) (OECD 201)⁴

EC₅₀ 72 h (growth rate/yield) > 18 mg/L

NOEC 72 h (growth rate/yield) = 18 mg/L (highest dose tested)

Crustacean (Daphnia magna)

Chronic Toxicity (OECD 211)⁵

NOEC 21 days (survival/growth/reproduction) = 2 mg/L (highest dose tested)

Fish (Fathead Minnow; Pimephales promelas)

Chronic Toxicity (OECD 210)⁶

NOEC 32 days/28 days post-hatch (survival) = 0.078 mg/L

NOEC 32 days/28 days post-hatch (hatching success/percent live and normal larvae/growth) = 3.1 mg/L

                                   

The PNEC for aquatic organisms is based on the lowest NOEC of 0.078 mg/L, noted in the fish chronic toxicity study.  An assessment factor of 10 is applied to the ecotoxicity base set of three chronic studies.

PNEC_aquatic = (0.078 mg/L)/10 = (78 µg/L)/10 = 7.8 µg/L

Environmental Risk Classification (PEC/PNEC Ratio)

PEC/ PNECaquatic = 0.00137/7.8 = 1.76 x 10^-4. PEC/ PNECaquatic < 0.1 which justifies the phrase “Use of mavacamten has been considered to result in insignificant environmental risk”

Degradation

Biotic degradation

Ready Degradability (OECD 301B)⁷:

8.40% biodegradation over 28 days; not readily biodegradable

Simulation Studies (OECD 308)⁸:

The rate and route of transformation for mavacamten was studied in two United States aquatic sediment systems: Taunton River and Weweantic River water/sediment test systems.  They were significantly different based on the texture and percentage organic carbon of the sediment. Water/sediment samples were analyzed at 0, 1, 2, 3, 14, 30, 65, and 101 days after treatment (DAT).  For each sampling interval, duplicate samples for each sediment type were removed from the test systems.  Sediment samples were extracted with 80/20 acetonitrile/purified reagent water (v/v) and 80/20/0.1 acetonitrile/purified reagent water/formic acid (v/v/v).  Extracts were analyzed by liquid scintillation counting (LSC) and high-performance liquid chromatography with radiometric detection (HPLC-RAM) for determination and profiling of major transformation products ≥10% applied radioactivity (% AR).  The post extracted sediment samples were combusted and analyzed by LSC for determination of non extractable residues.  Non extractable residues in representative samples were additionally characterized by extraction with polar and non-polar solvent and organic matter fractionation.  The volatile trapping solutions were analyzed by LSC for determination of ¹⁴CO₂ and volatile organics.  The presence of ¹⁴CO₂ in representative potassium hydroxide trapping solutions, containing >5% AR, was confirmed by barium chloride precipitation.

Average material balance was acceptable and ranged from 90.0 to 109% AR over the course of the study. In both aerobic sediment systems, mavacamten declined in the water phase over time (0% of initial concentration on day 101) and was observed in the sediment phase with 0.77-3.17% of initial radioactivity on day 101.  The half-life (DT₅₀) of mavacamten in water layer at 12°C for Taunton River and Weweantic River sediment systems was 2.04 and 2.86 days, respectively.  The total system half-life (DT₅₀)  of mavacamten at 12°C for Taunton River and Weweantic River sediment systems was 2.41 and 3.54 days, respectively. Note that the calcuations for total system half-life for both systems did not include NER which is considered not bioavailable as a range of extraction conditions were used to extract sediment residues.

Non-extractable residues (NER) increased over the course of the incubation period.  At the end of the study (101 DAT), the non-extractable residues in the test systems represented 69.7 and 70.4% AR for the Taunton River and Weweantic River test systems, respectively.  Since >10% AR was recovered in the non-extractable residues, additional characterization was performed by polar and non-polar solvent extractions and organic matter fractionation (OMF) for the DAT 101 samples.  Additional extractions with polar (tetrahydrofuran) and non-polar (hexane) solvents removed ≤0.63 and ≤0.07% AR for the Taunton River and Weweantic River test systems, respectively.  The highest percentage of the residual radioactivity observed from OMF was a maximum of 30.5% AR bound to the humin fraction for the Taunton River test system and 29.6% AR bound to the humin fraction for the Weweantic River test system.  The highest amount contained in the humic fraction was ≤23.8% AR. Ultimate biodegradation of [14C]mavacamten was observed in the aerobic samples with evolution of 14CO₂ reaching an average maximum of 9.45 and 11.5% AR for the Taunton River and Weweantic River aerobic test systems, respectively. 

Two transformation products did exceed 10% of applied radioactivity during the expsoure in both systems, and were identified as TP2 and TP4, respectively.  Both transformation products were not observed on Day 101. TP2 is proposed to be a sulfur-bound dimer of mavacamten with an IUPAC-consistent name of 6,6'-(sulfanediylbis{[1-phenylethyl]azanediyl}-di[3-(propan-2-yl)pyrimidine-2,4(1H,3H)-dione]).  TP4 may contain two compounds, one is called  [2,6-dioxo-1-(propan-2-yl)-1,2,3,6-tetrahydropyrimidin-4-yl]sulfamic acid and the other is either 2-(4-hydroxy-2,6-dioxotetrahydropyrimidin-1(2H)-yl)propanoic acid or 2-(2,6-dioxotetrahydropyrimidin-1(2H)-yl)-3-hydroxypropanoic acid.  The relative amounts of each cannot be determined by LC-MS alone due to potential differences in ionization efficiencies between the different structures.

Based on the OECD 301B study, mavacamten is not readily biodegradable.  Based on the DT₅₀s determined in the OECD 308 study and the 2012 FASS guidance for pharmaceutical companies v3.0, the phrase “mavacamten is degraded in the environment” is justified, given that DT₅₀ values are less than 32 d for the total systems and there is less than 15% remaining as parent compound at the end of the study.

Bioaccumulation

Partitioning Coefficient (OECD 107)⁹:

LogD_ow values at pH 5, 7 and 9 was reported as 2.92, 2.90 and 2.73, respectively.            

Justifiation of chosen bioaccumulation phrase:

Since logDow at pH 7 < 4, the phrase “mavacamten has low potential for bioaccumulation” is justified.

Soil Sorption/Desorption

Determination of the Koc Coefficient (OECD 106)¹⁰

An OECD 106 study was conducted in three soils with varying characteristics (pH, organic carbon, clay content and soil texture) and two sludges from different wastewater treatment plants.  Kocs in the three soils at equilibrium ranged from 243-395 L/kg.  The Kocs in the two sludges at equilibrium were 239 and 306 L/kg. 

PBT/vPvB Assessment

Mavacamten does not meet the criteria to be considered a PBT or vPvB substance.

References

1. 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

2. Camzyos (mavacamten) US Presicribing Information. https://packageinserts.bms.com/pi/pi_camzyos.pdf. Bristol Myers Squibb Revision date 06/2023 

3. Mavacamten - Activated Sludge Respiration Inhibition Test Following OECD Guideline 209 (Study No. 12534.6563) Bristol Myers Squibb One Squibb Drive, 2022,  Document Control Number 930203330

4. Mavacamten - 72-Hour Toxicity Test with the Freshwater Green Alga, Raphidocelis subcapitata, OECD 201, (Study No. 12534.6570), Bristol Myers Squibb, 2022, Document Control Number 930203378

5. Mavacamten - Chronic Toxicity Test to Water Fleas, Daphnia magna, Under Flow-Through Conditions OECD 211 (Study No. 12534.6565), Bristol Myers Squibb, 2023, Document Control Number 930203355

6. Mavacamten - Early Life-Stage Toxicity Test with Fathead Minnow (Pimephales promelas) OECD 210, (Study No. 12534.6564), Bristol Myers Squibb, 2023 Document Control Number 930203333

7. Mavacamten - Determination of the Biodegradability of a Test Substance Based on OECD Method 301B (CO₂ Evolution Test) (Study No. 12534.6562) Bristol Myers Squibb Company, 2022. Document Control Number 930203307

8. [¹⁴C]Mavacamten - Aerobic Transformation in Aquatic Sediment Systems Following OECD Guideline 308 (Study No. 12534.6574), Bristol Myers Squibb, 2023, Document Control Number 930209843

9. Mavacamten - Determining the Partitioning Coefficient (n-Octanol/Water) by the Shake-Flask Method Following OECD Guideline 107 (Study No. 12534.6553), Bristol Myers Squibb, 2022, Document Control Number 930203316

10. [¹⁴C]Mavacamten: Determining the Adsorption Coefficient (K_OC) Following OECD Guideline 106  (Study No. 12534.6561), Bristol Myers Squibb, 2023, Document Control Number 930203295