7-Cyclopentyl-N,N-dimethyl-2-{[5-(piperazin-1-yl)pyridin-2-yl]amino}-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide

Endpoint summary

Description of key information

Compared with the Cmax and AUC(0-72h) values at 100 mg/kg, the Cmax and AUC(0-72h) values

measured in the female dog at 150 mg/kg were slightly lower. This was mostly due to

vomiting with dose formulation resulting in lower uptake of the test item.

In conclusion, oral administration of single dosages of LEE011 at 25, 50, 100 and 150 mg/kg

to one male and one female Beagle dogs was well tolerated up to 25 (males) and 50 mg/kg

(females). Based on the slight to severe decreases in food consumption at ≥ 25 mg/kg and the

toxicokinetic parameters, a no-observable-effect-level (NOEL) was not established in this

study, whereas a single dose of 100 mg/kg LEE011 was considered to be the maximum

tolerable dose (MTD) in view of the pronounced emesis at ≥ 100 mg/kg.

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

2018

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 non-GLP study has been performed to the highest standards of scientific quality in
accordance with our Standard Operating Procedures. With the exception of inspections by
Quality Assurance and of a report audit, this study was conducted according to the basic
applicable requirements of GLP in Switzerland.

Qualifier:

no guideline followed

Principles of method if other than guideline:

The succinate salt of LEE011 (batch no. 0850001) was administered as single dosages of 25,
50, 100 and 150 mg/kg to Beagle dogs of 7.5 to 9.7 kg and 12 to 13 months of
age at start of dosing. The dose formulation was a suspension in a 0.5 % methylcellulose
aqueous solution w/v, (MC, low viscosity, M0430) using Nanopure water.

GLP compliance:

no

Remarks:

Study has been performed to the highest standards of scientific quality in accordance with our Standard Operating Procedures. With the exception of inspections by QA, this study was conducted according to the requirements of GLP in Switzerland.

Species:

dog

Strain:

other: Beagle dogs

Sex:

male/female

Details on test animals or test system and environmental conditions:

Beagle dogs of 7.5 to 9.7 kg and 12 to 13 months of age

Route of administration:

oral: gavage

Vehicle:

methylcellulose

Details on oral exposure:

The succinate salt of LEE011 (batch no. 0850001) was administered as single dosages of 25,
50, 100 and 150 mg/kg to Beagle dogs of 7.5 to 9.7 kg and 12 to 13 months of
age at start of dosing. The dose formulation was a suspension in a 0.5 % methylcellulose
aqueous solution w/v, (MC, low viscosity, M0430) using Nanopure water.

Doses:

Dosing days Dose Dosage volume Test item concentration No. of Animal no.
(mg/kg)* (ml/kg) (mg/ml)* animals /Sex
1 25 (31.8) 2 12.5 (15.9) 2 42M, 41F
7 50 (63.6) 2 25 (31.8) 2 42M, 41F
10 100 (127.2) 2 50 (63.6) 2 44M, 43F
15 150 (190.8) 2 75 (95.4) 2 44M, 43F
* Expressed in terms of the base. Equivalent dosages expressed in terms of the salt are given in parentheses (salt/base ratio: 1.272).
The following investigations were performed: mortality, clinical signs, body weight and food consumption. Blood was collected for toxicokinetics on each day of dosing at predose, 0.5, 1, 3, 7, 24, 48 and 72 hours postdose.

No. of animals per sex per dose:

Dosing days Dose Dosage volume Test item concentration No. of Animal no.
(mg/kg)* (ml/kg) (mg/ml)* animals /Sex
1 25 (31.8) 2 12.5 (15.9) 2 42M, 41F
7 50 (63.6) 2 25 (31.8) 2 42M, 41F
10 100 (127.2) 2 50 (63.6) 2 44M, 43F
15 150 (190.8) 2 75 (95.4) 2 44M, 43F
* Expressed in terms of the base. Equivalent dosages expressed in terms of the salt are given in parentheses (salt/base ratio: 1.272).
The following investigations were performed: mortality, clinical signs, body weight and food consumption. Blood was collected for toxicokinetics on each day of dosing at predose, 0.5, 1, 3, 7, 24, 48 and 72 hours postdose.

Control animals:

no

Details on study design:

The test item LEE011 (also referred to as ‘test article’) is a CDK4/6 (D-type cyclin-dependent
kinase) inhibitor. The purpose of this toxicity study in dogs was to establish the maximum
tolerable dose level of LEE011 after single administration to aid in the selection of
appropriate dose levels for a subsequent telemetry study.
The succinate salt of LEE011 (batch no. 0850001) was administered as single dosages of 25,
50, 100 and 150 mg/kg to Beagle dogs of 7.5 to 9.7 kg and 12 to 13 months of
age at start of dosing. The dose formulation was a suspension in a 0.5 % methylcellulose
aqueous solution w/v, (MC, low viscosity, M0430) using Nanopure water.
The following investigations were performed: mortality, clinical signs, body weight and food
consumption. Blood was collected for toxicokinetics on each day of dosing at predose, 0.5, 1,
3, 7, 24, 48 and 72 hours postdose.

Key result

Sex:

male/female

Dose descriptor:

other: maximum tolerable dose (MTD)

Effect level:

100 mg/kg bw

Based on:

test mat.

Remarks on result:

other: no-observable-effect-level was not established in this study

Mortality:

No mortality occurred.

Clinical signs:

other: The main treatment-related clinical sign was dose-dependent emesis with dose formulation and mucus at ≥ 50 mg/kg in males and at ≥ 100 mg/kg in females. Frequency and intensity increased in a dose-dependent manner. At 100 mg/kg, both the male and female s

Other findings:

Food consumption:
Slight to severe decreases in food consumption were observed on days of dosing up to 4 days
postdose at ≥ 25 mg/kg. There was no clear dose dependency and overall food consumption
showed moderate to high variability including during pretest.

Toxicokinetics

All animals (1 dog per sex per dose) receiving LEE011 were exposed to the parent drug with

the individual time to reach the highest plasma concentration (Tmax) generally observed

between 0.5-7 h postdose regardless of the dose.

For LEE011 and LEQ803 the exposure in general increased with increasing dose in an underproportional

manner in terms of AUC over the dosing regimen.

No clear conclusion on gender difference based on the exposure data could be made in view

of the low number of animals investigated.

The percentage of LEQ803 compared with LEE011 based on AUC(0-72h) was between 5-14 %.

Positive values were measured for time point 0 h in some profiles due to insufficient wash-out

period following the previous dose applied to the respective dogs. However, the positive 0 h

values accounts for 0.04-0.1 % for LEE011 and 0.4-0.9 % for LEQ803 when compared with

the corresponding Cmax. Therefore, the impact of the positive 0 h values on the results is

negligible.

Interpretation of results:

study cannot be used for classification

Conclusions:

Compared with the Cmax and AUC(0-72h) values at 100 mg/kg, the Cmax and AUC(0-72h) values
measured in the female dog at 150 mg/kg were slightly lower. This was mostly due to
vomiting with dose formulation resulting in lower uptake of the test item.
In conclusion, oral administration of single dosages of LEE011 at 25, 50, 100 and 150 mg/kg
to one male and one female Beagle dogs was well tolerated up to 25 (males) and 50 mg/kg
(females). Based on the slight to severe decreases in food consumption at ≥ 25 mg/kg and the
toxicokinetic parameters, a no-observable-effect-level (NOEL) was not established in this
study, whereas a single dose of 100 mg/kg LEE011 was considered to be the maximum
tolerable dose (MTD) in view of the pronounced emesis at ≥ 100 mg/kg.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Acute toxicity: via inhalation route

Endpoint conclusion

Endpoint conclusion:

no study available

Acute toxicity: via dermal route

Endpoint conclusion

Endpoint conclusion:

no study available

Justification for classification or non-classification

Single dose toxicity study (Dogs), Route of administration: Oral, 25 mg/kg, 50 mg/kg, 100 mg/kg, 150 mg/kg,

showed that the substance was:

- Well tolerated at 25 (males) and 50 mg/kg (females).

- The main treatment-related clinical sign was dose-dependent emesis of the dose formulation and mucus.

- The MTD was 100 mg/kg.