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

Endpoint summary

Link to relevant study record(s)

Reference

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

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