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GlaxoSmithKline

Depottablett 600 mg
(Beige, filmdragerade, bikonvexa, ovala tabletter cirka 19 mm långa, 10 mm breda och 8 mm tjocka och präglade med ”SV 1V7” på ena sidan.)

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ATC-kod: J05AX29
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  • Vad är miljöinformation?

Miljöinformation

Miljöpåverkan

Fostemsavir

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


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Detaljerad miljöinformation


Fostemsavir

Environmental risk: Use of fostemsavir has been considered to result in insignificant environmental risk.

Degradation: Fostemsavir is potentially persistent.

Bioaccumulation: Fostemsavir has low potential for bioaccumulation.


Detailed background information

Fostemsavir is a pro-drug that is converted to temsavir in patients and as a consequence the drug substance of interest entering the environment is temsavir and is the focus of interest for this environmental risk assessment.


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)

PEC = 0.0015 μg/L


Where:


A = 1.0 – 10 kg (market forecast range for API, Temsavir, in Sweden year 2023, data from GSK Manufacturing Strategy). The upper range, 10 kg, has been used in the PEC calculation.


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 = 9 *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 (Pseudokirchneriella subcapitata):

NOEC 96h (growth = 9,800 μg/L (OECD 201) (Reference 3)


Water flea (Daphnia magna):

Acute toxicity

No data


Water flea (Daphnia magna):

Chronic toxicity

NOEC 21 days (reproduction) = 8,900 μg/L (OECD 211) (Reference 4)


Rainbow Trout:

Acute toxicity

No data


Fathead Minnow (Pimephales promelas):

Chronic toxicity

NOEC 33 days (development) = 560 μg/L (OECD 210) (Reference 5)


Other ecotoxicity data:

Chironomid (Chironomus riparius)

NOEC 28 days (development) = 50,000 μg/kg (OECD 218) (Reference 6)


Microorganisms in activated sludge

EC50 3 hours (Inhibition) = 1,000,000 μg/L (OECD 209) (Reference 7)


PNEC = 560/10 = 56 μg/L


PNEC (μg/L) = lowest NOEC/10, where 10 is the assessment factor applied for three long-term NOECs. NOEC for fish (= 560 ug/L) 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 = 0.0015/560 = 2.68 x 10-6, i.e. PEC/PNEC ≤ 0.1 which justifies the phrase “Use of fostemsavir has been considered to result in insignificant environmental risk.”


Degradation


Biotic degradation


Ready degradability:

21.24% ultimate degradation (DOC) in 28 days (OECD 302B) (Reference 8)


Inherent degradability:

No data


Simulation studies:


Water-sediment study:


Total System: 50% (DT50) dissipation in = 53-82 days (OECD 308) (Reference 9)

Non-extractable residue (Day 100) = 45% - 51.80%


Sediment samples were extracted once with approximately 150 mL of 80/20 acetonitrile/purified reagent water (v/v), and placed on a shaker table at approximately 150 rpm for 10 minutes and then centrifuged at approximately 1000 rpm for 10 minutes. The sample extracts were transferred to a graduated cylinder, the volume recorded and analyzed by LSC (2 × 1.0 mL). The extraction procedure was repeated times for each sampling interval as described above; once using 80/20/0.1 acetonitrile/purified reagent water/formic acid (v/v/v) and once using 80/20/0.5 acetonitrile/purified reagent water/formic acid (v/v/v) for a total of three extractions.


In summary, most of the radioactivity remaining after fractionation was characterized as being bound to the fulvic fraction (i.e., 61.25 and 39.67% AR, for the Taunton River and Weweantic River, respectively).


Abiotic degradation


Hydrolysis:

No data


Photolysis:

No data


Justification of chosen degradation phrase:

Fostemsavir is not readily biodegradable nor inherently biodegradable. This substance is predicted to degrade in water sediment systems ≥ 50 days. Non-extractable residues represent 45% - 51.80% of the total material. The phrase “Fostemsavir is potentially persistent” is thus chosen.


Bioaccumulation


Partitioning coefficient:

Log Dow = 1.60 at pH 7 (OECD 107) (Reference 10)


Log Dow at pH 5 = 1.59

Log Dow at pH 7 = 1.60

Log Dow at pH 9 = 0.981


Justification of chosen bioaccumulation phrase:

Since log Dow < 4 at pH 7, the substance has low potential for bioaccumulation.


Excretion (metabolism)

Fostemsavir is a prodrug that is metabolised to temsavir by alkaline phosphatase at the luminal surface of the small intestine and is generally not detectable in plasma following oral administration. The active moiety, temsavir, is readily absorbed with the median time to maximal plasma concentrations (Tmax) at 2 hours post dose (fasted).


Temsavir is absorbed across the small intestine and caecum/proximal ascending colon. In vivo, temsavir is primarily metabolised via esterase hydrolysis (36.1% of administered dose) and secondarily by CYP3A4-mediated oxidative (21.2% of administered dose) pathways. Other non-CYP3A4 metabolites account for 7.2% of the administered dose. Glucuronidation is a minor metabolic pathway (<1% of administered dose). Temsavir is extensively metabolised, accounting for the fact that only 3% of the administered dose is recovered in human urine and faeces. Temsavir is biotransformed into two predominant circulating inactive metabolites,
BMS-646915 (a product of hydrolysis) and BMS-930644 (a product of N-dealkylation).


Temsavir has a terminal half-life of approximately 11 hours. Plasma temsavir clearance following intravenous administration was 17.9 L/hr, and the apparent clearance (CL/F) following oral administration was 66.4 L/hr. After oral administration of a single 300 mg dose of 14C-labelled fostemsavir in a human mass balance study, 51% and 33% of the radioactivity was retrieved in the urine and faeces, respectively. Based on limited bile collection in this study (3 to 8 hours post dose), biliary clearance accounted for 5% of the radioactive dose, suggesting that a fraction of the faecal excretion is from biliary excretion. (Reference 2).


PBT/vPvB assessment

Fostemsavir does not fulfil the criteria for PBT and/or vBvP.


All three properties, i.e. ‘P’, ‘B’ and ‘T’ are required in order to classify a compound as PBT (Reference 1). Fostemsavir does not fulfil the criteria for PBT and/or vBvP based on log Dow < 4.


Please, also see Safety data sheets on http://www.msds-gsk.com/ExtMSDSlist.asp.


References


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

  2. Pharmacokinetic properties: Metabolism and Elimination. Summary of Product Characteristics. Rukobia EPAR Product Information, European Medicines Agency, February 2021.

  3. Softcheck, K.A.; BMS-626529-02 − 72-Hour Toxicity Test with the Freshwater Green Alga, Pseudokirchneriella subcapitata; Smithers Viscient Study Number 12534.6469; June 10, 2016.

  4. Lauze, J.F.; BMS-626529-02 – Full Life-Cycle Toxicity Test with Water Fleas, Daphnia magna; Smithers Viscient Study Number 12534.6474; July 01, 2016.

  5. Sayers, L.E.; BMS-626529-02 – Early Life-Stage ToxicityTest with Fathead Minnow (Pimephales promelas); Smithers Viscient Study Number 12534.6473; July 18, 2016.

  6. Bradley, M.J.; [14C]BMS-626529-05 - Toxicity Test with Sediment-Dwelling Midges (Chironomus riparius); Smithers Viscient Study Number 12534.6479; September 22, 2016.

  7. Griffith, A.W.; BMS-626529-02 - Activated Sludge Respiration Inhibition Test; Smithers Viscient Study Number 12534.6472; June 01, 2016.

  8. Griffith, A.W.; Determination of the Biodegradability of BMS-626529-02 Based on OECD Method 301B (CO2 Evolution Test); Smithers Viscient Study Number 12534.6475; June 06, 2016.

  9. Hatch, D.; [14C]BMS-626529-05 – Aerobic Transformation in Aquatic Sediment Systems Following OECD Guideline 308; Smithers Viscient Study Number 12534.6477; November 07, 2016.

  10. McClean, S.; BMS-626529-02 - Determining the Partitioning Coefficient (n-Octanol/Water) by the Shake-Flask Method; Smithers Viscient Study Number 02571-1037; July 29, 2016.