tert-Butyl 4-({6-[7-cyclopentyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl]amino}pyridin-3-yl)piperazine-1-carboxylate

Endpoint summary

Link to relevant study record(s)

Reference

Endpoint:

basic toxicokinetics in vitro / ex vivo

Type of information:

other: theoretical assessment

Adequacy of study:

key study

Study period:

not applicable

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

test procedure in accordance with generally accepted scientific standards and described in sufficient detail

Justification for type of information:

This theoretical assessment was prepared, taking all currently available relevant information into account, based on the REACH Guidance: Guidance on Information Requirements and Chemical Safety Assessment, Chapter R.7c Endpoint specific guidance.

Objective of study:

absorption

distribution

metabolism

Qualifier:

according to guideline

Guideline:

other: REACH Guidance: Guidance on Information Requirements and Chemical Safety Assessment, Chapter R.7c Endpoint specific guidance

Principles of method if other than guideline:

REACH Guidance: Guidance on Information Requirements and Chemical Safety Assessment, Chapter R.7c Endpoint specific guidance

GLP compliance:

yes

Radiolabelling:

no

Details on study design:

A toxicokinetic assessment was performed based on the available data of the substance.

Preliminary studies:

A toxicokinetic assessment was performed based on the available data of the substance.

Details on absorption:

The major routes by which a substance can enter the body are the gastrointestinal tract, the
lungs, and the skin. Since different parameters are relevant for absorption via the different
routes of exposure, the uptake via these three routes will be addressed individually.
After oral administration, in general, a compound needs to be dissolved before it can be taken
up from the gastrointestinal tract1. Since the water solubility of LEE011-A3 is very low
(0.246 mg/L at 20°C), the substance is expected to dissolve only to a limited extent into the
gastrointestinal fluids. Based on its molecular weight (534.7), uptake via passive diffusion
(passage of small water-soluble molecules through aqueous pores or carriage across
membranes with the bulk passage of water) is expected to be limited. LEE011-A3 has a
moderate partition coefficient (log Pow = 3.8 at pH 7). Considering also the poor water
solubility of the substance, passive diffusion (which allows crossing of epithelia) is unlikely
to occur, but uptake via micellular solubilisation may take place. Since no data are available
on the dissociation constant of LEE011-A3, it is unclear in which state (ionised or not
ionised) the substance will be present under physiological circumstances in the
gastrointestinal tract. Since it is generally thought that ionised substances do not readily
diffuse across biological membranes, the state of the substance might hamper its uptake.
For risk assessment purposes oral absorption of LEE011-A3 is set at 10%, based on its very
low water solubility, its high molecular weight and its moderate partition coefficient. The oral
toxicity data do not provide reasons to deviate from the proposed oral absorption factor.2

LEE011-A3 has a medium vapour pressure of 0.84 μPa at 20°C, which indicates that the
substance is not volatile and exposure via vapour will be limited. On the other hand, LEE011-
A3 is a powder. In humans, particles with aerodynamic diameters below 100 μm have the
potential to be inhaled. Particles with aerodynamic diameters below 50 μm may reach the
thoracic region, and below 15 μm can reach the alveolar region. The median particle size of
LEE011-A3 is 7 μm, which is indicative that the compound have the potential to be inhaled
and could reach the alveolar region. Once inhaled, it will get in contact with nasopharyngeal
region and trigger sneezing and cough, which will enhance its elimination. Moreover, due to
its low water solubility, LEE011-A3 will not easily dissolve in the mucus lining the
respiratory tract and further absorption via this route is unlikely. However, since this
substance is a powder, it can accumulate in the respiratory tract and be cleared by the
mucocilliary mechanism and swallowed, reaching gastrointestinal tract. A small amount of
powder may be taken up by phagocytosis and transported to the blood or lymphatic system or
being engulfed by macrophages in the alveolar area. Furthermore, LEE011-A3 has a log Pow
3.8 at pH 7 and therefore may cross biological membranes. Taking these considerations
together it is concluded that for risk assessment purposes as a worst case the inhalation
absorption of LEE011-A3 should be set at 100%.2
LEE011-A3 is a powder with very low water solubility, it will only dissolve to a very small
extent into the surface moisture of the skin to allow uptake. Since the partition coefficient (log
Pow 3.8 at pH 7) and the molecular weight is 534.7, therefore the substance specific data do
not meet the criteria for 10% dermal absorption as given in Endpoint Specific Guidance
(MW>500 and log P outside the range -1 and 4). LEE011-A3 is neither skin irritating nor
corrosive. However, it is mildly skin sensitizer, indicating that there is absorption in some
extent. Considering also that it is generally accepted that dermal absorption is not higher than
oral absorption, a 10% skin absorption is considered for LEE011-A3 for risk assessment
purposes.2

Details on distribution in tissues:

Once absorbed, distribution of the substance throughout the body is expected to be moderate
based on its very low water solubility, moderate log Pow and high molecular weight.
Absorbed LEE011-A3 may be metabolized in the gastrointestinal tract or the liver. Excretion
can take place through bile and urine.3 Based on its moderate partition coefficient (log Pow =
3.8 at pH 7), LEE011-A3 might accumulate in adipose tissue (intracellular concentration may
be higher than the extracellular concentration) to some extent. However, based on its very low
water solubility and high molecular weight, the overall bioaccumulation potential of LEE011-
A3 is expected to be low.

Metabolites identified:

not specified

Conclusions:

Based on the physical/chemical and toxicological properties of the substance, absorption
factors for this substance are derived to be 10% (oral), 100% (inhalation) and 10% (dermal)
for risk assessment purposes. The bioaccumulation potential is expected to be low.

Description of key information

Based on the physical/chemical and toxicological properties of the substance, absorption

factors for this substance are derived to be 10% (oral), 100% (inhalation) and 10% (dermal)

for risk assessment purposes. The bioaccumulation potential is expected to be low.