Detaljerad miljöinformation

Detailed background information

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) = 1.5*10^-6*A*(100-R)

Where:

A (kg/year) = total actual API sales (active moiety) in Sweden for the most recent year (will be obtained from LIF).

R (%) = removal rate (due to loss by adsorption to sludge particles, by volatilization, hydrolysis or biodegradation = 0 if no data is available)

P = number of inhabitants in Sweden = 9*10⁶

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

D = factor of dilution of waste water by surface water flow = 10 (Ref 1)

PEC calculation for meropenem

A = 445.55 kg

R = 0

PEC (µg/l) = 1.5*10^-4*A = 0.067 μg/L

Predicted No Effect Concentration (PNEC)

Ecotoxicological studies

Algae (Cyanobacterium, Anabaena flos-aquaea)
NOEC 72 hours (growth rate) = 0.015 mg/L = 15 μg/L
EC₅₀ 72 hours (growth rate) = 0.026 mg/L = 26 μg/L
Guideline: OECD 201
(Ref II)

Crustacean (Daphnia magna)
Acute toxicity
EC₅₀ 48 hours (immobility) = > 900 mg/L = 900 000 μg/L
Guideline: FDA Technical Assistance Document 4.08
(Ref II)

Other ecotoxicity data:

PNEC = 1.5 μg/L (to calculate the PNEC from an anti-microbial effect study with cyanobacteria, a default assessment factor of 10 is applied to the NOEC).
(Ref III)

PNEC (μg/L) = lowest NOEC/10, where 10 is the assessment factor used.

NOEC for Anabaena flos-aquae has been used for this calculation since it is the most sensitive of the two tested species.

Environmental Risk Classification (PEC/PNEC ratio)

PEC/PNEC = 0.067/1.5 = 0.044

PEC/PNEC ≤ 0.1

Summary phrases for the environmental risk:

Use of meropenem has been considered to result in insignificant environmental risk.

Degradation
Meropenem is not rapidly biologically degraded, but it is prone to undergo hydrolysis with reported half lives of 63 hours (pH 7) and 12 minutes (pH 9).
(Ref IV)

Justification of chosen degradation phrase: 
Meropenem is potentially persistent.

Bioaccumulation

Partitioning coefficient:

log P: -0.6 (experimental, source not available, pH unknown)
 (Ref V)

Justification of chosen bioaccumulation phrase: 
Since log P < 4, the substance has low potential for bioaccumulation.

Excretion (metabolism)
 Meropenem is mostly eliminated unchanged. About 25% of the administered dose is eliminated as the inactive open ring form.

Meropenem is primarily excreted via the kidneys. Approximately 40-60% of a meropenem dose is excreted unchanged within 24 - 48 hours with a further 25% recovered as the microbiologically inactive hydrolysis product. The elimination of meropenem by the kidneys resulted in high therapeutic concentrations in urine. The mean renal clearance for meropenem was 7.7 L/h. The mean non-renal clearance for meropenem was 4.8 L/h, which comprises both fecal elimination (~2% of the dose) and degradation due to hydrolysis.

(Ref VI)

References
I. ECHA, European Chemicals Agency. 2008 Guidance on information requirements and chemical safety assessment, find here.

II. Environmental Risk Assessment Data of Meropenem, retrieved 2020-08-27 at Astra Zeneca webpage, find here.

III. Environmental classification of pharmaceuticals at www.fass.se; Guidance for pharmaceutical companies. 2012

IV. Internal document, Environmental Risk Assessment for Meropenem-Vaborbactam. 2018-02-20. 

V. DrugBank - Meropenem. Retrieved 2020-08-27 from DrugBank webpage, find here)

VI. Vaborem SmPC, retrieved 2020-08-27 from EMA webpage, find here.

Detaljerad miljöinformation

Detailed background information

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) = 1.5*10^-6*A*(100-R)

Where:

A (kg/year) = total actual API sales (active moiety) in Sweden for the most recent year (will be obtained from LIF).

However, for newly introduced products (on patent), it is recommended to use the forecasted sales five years after launch when calculating the environmental risk.

A = 21 kg.
Forecasted sales of vaborbactam in Sweden five years after launch is estimated to be 21 kg (using 250 patients on 2 g dosing scheme for 14 days and with CrCl ≥40 ml/min).

R (%) = removal rate (due to loss by adsorption to sludge particles, by volatilization, hydrolysis or biodegradation = 0 if no data is available)

P = number of inhabitants in Sweden = 9*10⁶

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

D = factor of dilution of waste water by surface water flow = 10 (Ref 1)

PEC calculation for vaborbactam

A = 21 kg (estimated value)

R = 0

PEC (µg/l) = 1.5*10^-4*A = 0.00315 μg/L

Predicted No Effect Concentration (PNEC)

Ecotoxicological studies

Algae (Cyanobacterium, Anabaena flos-aquaea)
NOEC 72 hours (growth inhibition) = 25 mg/L = 25 000 μg/L
Guideline: OECD 201
(Ref II)

Crustacean (Daphnia magna)
NOEC 21 days (reproduction test) = 10.9 mg/L = 10 900 μg/L
Guideline: OECD 211
(Ref II)

Fish (Fathead Minnow, Pimephales promelas)
 NOEC 28 days (Early Life Stage Test) = 11.5 mg/L = 11 500 μg/L
 Guideline: OECD 210
(Ref II)

Other ecotoxicity data:

PNEC = 1090 μg/L (to calculate the PNEC from an anti-microbial effect study with cyanobacteria, a default assessment factor of 10 is applied to the NOEC).
(Ref III)

PNEC (μg/L) = lowest NOEC/10, where 10 is the assessment factor used.

NOEC for Crustacean (Daphnia magna) has been used for this calculation since it is the most sensitive of the three tested species.

Environmental Risk Classification (PEC/PNEC ratio)

PEC/PNEC = 0.00315/1090 = 2.9 x 10 ^-6

PEC/PNEC ≤ 0.1

Summary phrases for the environmental risk:

Use of vaborbactam has been considered to result in insignificant environmental risk.

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

Degradation

Vaborbactam is expected to be not easily biodegradable and assumed to be stable under typical environmental conditions.
(Ref II)

Justification of chosen degradation phrase:

Vaborbactam is potentially persistent.

Bioaccumulation

Partitioning coefficient:

log Kow: -2.68 (shake flask method, pH 7)
Guideline: OECD 107.

(Ref II)

Justification of chosen bioaccumulation phrase: 
Since log Kow < 4, the substance has low potential for bioaccumulation.

Excretion (metabolism)
 Vaborbactam does not undergo metabolism.

Vaborbactam is primarily excreted via the kidneys. Approximately 75 to 95% of vaborbactam is excreted unchanged in the urine over a 24 - 48 hour period. The elimination of vaborbactam by the kidneys resulted in high concentrations in the urine.

(Ref IV)

References

I. ECHA, European Chemicals Agency. 2008 Guidance on information requirements and chemical safety assessment, find here.

II. Internal document, Environmental Risk Assessment for Meropenem-Vaborbactam.
2018-02-20.

III: Environmental classification of pharmaceuticals at www.fass.se; Guidance for pharmaceutical companies. 2012.

IV. Vaborem SmPC, retrieved 2020-08-27 from EMA webpage, find here.