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Diss Factsheets
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EC number: 807-111-0 | CAS number: 1211441-98-3
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data
Endpoint summary
Administrative data
Link to relevant study record(s)
- Endpoint:
- basic toxicokinetics in vivo
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- Nov 2018
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
- Objective of study:
- absorption
- distribution
Reference
Description of key information
IV: high plasma concentration in the mouse (43 mL/min/kg), rat (46 mL/min/kg), dog (32 mL/min/kg) and monkey (35 mL/min/kg) compared to hepatic blood flow. The plasma volume of distribution at steady-state (Vss) was large across species (7.9 to 28 L/kg) and the terminal elimination T1/2 was moderate in rodents and monkeys (~2 to 5 h) and longer in dogs (18 h) after i.v. administration.
Following oral dosing, Tmax occurred between 2 and 4 h in mice, rats, dogs and cynomolgus monkeys. In the rat, absorption (66.0%) was higher than bioavailability (37.1%), indicating a moderate first-pass effect.
Human data
LEE011 is rapidly absorbed with median time to reach maximum plasma concentrations (Tmax) ranging from 1 to 4 hours (range of median Tmax values). LEE011 plasma exposure (maximum plasma concentration [Cmax] and AUC) exhibit slightly over-proportional increases in exposure across the dose range tested (50 to 1200 mg), with no clear evidence of time-dependent auto-inhibition of its clearance mediated by CYP3A4. Steady-state is generally reached by Day 8 and the arithmetic mean effective T1/2 based on accumulation ratio (i.e., T1/2,acc) range from 15.9 to 43.1, hours across the 50 to 1200 mg dose cohorts. The accumulation ratio based on AUC obtained in a dosing interval (Racc) across the studied doses ranged from 1.55- to 3.13-fold.
Based on in vitro data, LEE011 is primarily metabolized by CYP3A4. Based on clinical data, ritonavir (a strong CYP3A4 inhibitor) and rifampicin (a strong CYP3A4 inducer) markedly increased and decreased LEE011 exposure, respectively. Therefore, drugs that are strong inhibitors or inducers of CYP3A4 should not be co-administered with LEE011.
Accumulation:
In the ongoing first in human study [CLEE011X2101] in
patients with advanced cancer, the effective half-life of LEE011 was estimated to range from 16 to 43 hours based on drug accumulation.
Key value for chemical safety assessment
- Bioaccumulation potential:
- low bioaccumulation potential
- Absorption rate - oral (%):
- 66
Additional information
Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.
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