Chemical formula: C₃₁H₃₄F₂N₆O₂ Molecular mass: 560.65 g/mol PubChem compound: 25141092
Entrectinib is an inhibitor of the tropomyosin receptor tyrosine kinases TRKA, TRKB and TRKC (encoded by the neurotrophic tyrosine receptor kinase [NTRK] genes NTRK1, NTRK2 and NTRK3, respectively), proto-oncogene tyrosine-protein kinase ROS (ROS1), and anaplastic lymphoma kinase (ALK), with IC50 values of 0.1 to 2 nM. The major active metabolite of entrectinib, M5, showed similar in vitro potency and activity against TRK, ROS1, and ALK.
Fusion proteins that include TRK, ROS1 or ALK kinase domains drive tumourigenic potential through hyperactivation of downstream signalling pathways leading to unconstrained cell proliferation. Entrectinib demonstrated in vitro and in vivo inhibition of cancer cell lines derived from multiple tumour types, including subcutaneous and intracranial tumours, harbouring NTRK, ROS1, and ALK fusion genes.
Prior treatments with other drugs that inhibit the same kinases may confer resistance to entrectinib. Resistance mutations in the TRK kinase domain identified following entrectinib discontinuation include NTRK1 (G595R, G667C) and NTRK3 (G623R, G623E and G623K). Resistance mutations in the ROS1 kinase domain identified following entrectinib discontinuation include G2032R, F2004C and F2004I.
The molecular causes for primary resistance to entrectinib are not known. It is therefore not known if the presence of a concomitant oncogenic driver in addition to an NTRK gene fusion affects the efficacy of TRK inhibition.
The pharmacokinetic parameters for entrectinib and its major active metabolite (M5), have been characterised in patients with NTRK gene fusion-positive solid tumours and ROS1-positive NSCLC and healthy subjects. The pharmacokinetics of entrectinib and M5 are linear and are not dose- dependent or time-dependent. Steady state is achieved within one week for entrectinib and two weeks for M5 following daily administration of entrectinib.
Entrectinib is a weak P-gp substrate based on in vitro data. The exact in vivo contribution of P-gp is unknown. M5 is a P-gp substrate. Entrectinib is not a substrate of BCRP but M5 is a substrate of BCRP. Entrectinib and M5 are not substrates of OATP 1B1 or OATP1B3.
Following a single 600 mg oral administration of entrectinib to patients with NTRK gene fusion-positive and ROS1-positive NSCLC under fed conditions, entrectinib was rapidly absorbed reaching time-to-maximum plasma concentration (Tmax) after approximately 4 to 6 hours. Based on population pharmacokinetic analysis, steady-state was achieved within 5 days for entrectinib with 600 mg once daily dosing.
No clinically significant effect of food on entrectinib bioavailability was observed.
In healthy adult subjects, the AUC and Cmax of entrectinib in the film-coated granule formulation was similar to that of the capsules. Entrectinib capsules administered as a suspension with water or milk, given orally, or through a gastric or nasogastric tube, results in similar AUC and Cmax as capsules swallowed whole.
Entrectinib and its major active metabolite M5 are highly bound to human plasma proteins independent of drug concentrations. In human plasma, entrectinib and M5 had similar protein binding with >99% bound at a clinically relevant concentration.
After a single oral dose of entrectinib, the geometric mean volume of distribution (Vz/F) was 600 L, suggesting extensive distribution of the drug. Entrectinib demonstrated steady-state brain-to-plasma concentration ratios of 0.4 to 2.2 in multiple animal species (mice, rats, and dogs) at clinically relevant systemic exposures.
Entrectinib is metabolised predominantly by CYP3A4 (~76%). Minor contributions from several other CYPs and UGT1A4 were estimated at <25% in total. The active metabolite M5 (formed by CYP3A4) and the direct N-glucuronide conjugate, M11, (formed by UGT1A4) are the two major circulating metabolites identified.
The population PK model estimated mean accumulation at steady-state following 600 mg once daily administration of entrectinib was 1.89 (±0.381) and 2.01 (±0.437) for M5. Following administration of a single dose of [14C]-labelled entrectinib, 83% radioactivity was excreted in faeces (36% of the dose as unchanged entrectinib and 22% as M5) with minimal excretion in urine (3%).
Entrectinib and M5 account for approximately 73% of radioactivity in systemic circulation at Cmax, and approximately half of total radioactivity AUCinf.
Population PK analysis estimated apparent clearance CL/F was 19.6 L/h and 52.4 L/h for entrectinib and M5, respectively. The elimination half-lives of entrectinib and M5 were estimated to be 20 hours and 40 hours, respectively.
Entrectinib has linear pharmacokinetics in the dose range of 100 mg to 600 mg.
The pharmacokinetics of entrectinib have been evaluated in 78 paediatric patients above one month of age. In patients from >1 month to ≤6 months the administered dose was 250 mg/m²; in patients >6 months, the administered dose was 300 mg/m² based on five BSA categories, with a maximum dose of 600 mg for children with ≥1.51 m² body surface area (BSA).
Data obtained from population pharmacokinetic analyses show that in paediatric patients 6 years and older, 300 mg entrectinib once daily dose for BSA range 0.81 m² to 1.10 m², 400 mg entrectinib once daily dose for BSA range 1.11 m² to 1.50 m², and 600 mg entrectinib once daily dose for BSA range ≥1.51 m² results in a similar systemic exposure attained in adults treated with 600 mg entrectinib once daily dose.
Data from non-compartmental analysis in patients from 1 month to <6 years demonstrated that systemic exposure of the sum of entrectinib and M5 in paediatric patients receiving 250 mg/m² or 300 mg/m² of entrectinib once daily were generally lower than the mean systemic exposure of adult patients treated with 600 mg of entrectinib once daily. The recommended dose in this age category is based on available efficacy and safety data.
No differences in entrectinib exposure were noted in patients older than 65 years and younger adults based on pharmacokinetic analysis.
Negligible amounts of entrectinib and the active metabolite M5 are excreted unchanged in urine (~3% of the dose) indicating that renal clearance plays a minor role in the elimination of entrectinib. Based on population pharmacokinetic analyses, the pharmacokinetics of entrectinib are not significantly affected in renal impairment. The impact of severe renal impairment on the pharmacokinetics of entrectinib is unknown.
The pharmacokinetics of entrectinib were studied in subjects with mild (Child-Pugh A), moderate (Child-Pugh B) and severe (Child-Pugh C) hepatic impairment, relative to subjects with normal hepatic function. Following administration of a single oral dose of 100 mg entrectinib, the combined AUClast of entrectinib and M5 showed no relevant change in the hepatic impaired groups compared to the normal function group. The AUClast geometric mean ratio (90% CI) was 1.30 (0.889, 1.89) for the mild, 1.24 (0.886, 1.73) for the moderate, and 1.39 (0.988, 1.95) for the severe hepatic impaired groups compared to the normal hepatic function group. For the unbound entrectinib and M5, the AUClast (fu) geometric mean ratio (90% CI) was 1.91 (1.21, 3.02) for the mild, 1.57 (1.06, 2.31) for the moderate, and 2.34 (1.57, 3.48) for the severe hepatic impaired groups compared to the normal hepatic function group. Although the effect of hepatic impairment on unbound PK parameters generally followed a similar direction as total PK parameters, due to the high non-specific binding in buffer and high variability, results should be interpreted with caution.
In addition, it was also observed that the variability in systemic exposure was high and observed exposures overlapped across all the study groups.
No clinically significant differences in the pharmacokinetics of entrectinib were observed based on sex, race (Asian, Black and White) and body weight (4 kg to 130 kg).
No carcinogenicity studies have been performed to establish the carcinogenic potential of entrectinib.
Entrectinib was not mutagenic in vitro in the bacterial reverse mutation (Ames) assay but demonstrated a potential for abnormal chromosome segregation (aneugenicity) in cultured human peripheral blood lymphocytes. Entrectinib was not clastogenic or aneugenic in the in vivo micronucleus assay in rats and did not induce DNA damage in a comet assay in rats.
Dedicated fertility studies in animals have not been performed to evaluate the effect of entrectinib. No adverse effects of entrectinib on male and female reproductive organs were observed in the repeat-dose toxicology studies in rats and dogs at approximately 2.4-fold and 0.6-fold, respectively, the human exposure by AUC at the recommended human dose.
In an embryo-foetal developmental study in rats, maternal toxicity (decreased body weight gain and food consumption) and foetal malformations (including body closure defects and malformations of the vertebrae and ribs), were observed at 200 mg/kg/day of entrectinib which represents approximately 2-fold the human exposure by AUC at the recommended dose. Dose-response dependent reduced foetal body weight (low, middle and high dose) and reduced skeletal ossification (middle and high dose) were observed at exposures equivalent to <2 times the human exposure by AUC at the recommended dose.
Entrectinib-related toxicities in repeat-dose studies in adult rats and dogs, and juvenile rats were observed in the central nervous system (convulsions, abnormal gait, tremors) at ≥0.2 times the human exposures by Cmax at the recommended dose, skin (scabs/sores) and decreased red blood cell parameters at ≥0.1 times the human exposure by AUC at the recommended dose. In adult rats and dogs, effects on liver (increased ALT and hepatocellular necrosis) were observed at ≥0.6 times the human exposure by AUC at the recommended dose. In dogs, diarrhoea at ≥0.1 times the human exposure by AUC at the recommended dose and prolongations of QT/QTc interval at ≥0.1 times the human exposure by Cmax at the recommended dose were also observed.
In a 13-week juvenile rat toxicology study, animals were dosed daily from post-natal day 7 to day 97 (approximately equivalent to neonate to adulthood in humans). In addition to CNS effects, ptosis and skin effects, decreased RBC parameters and effects on growth and development were observed in the dosing and recovery phases including decreased body weight gain and delayed sexual maturation (at ≥4 mg/kg/day, approximately 0.1 times the human exposure by AUC at the recommended dose). Deficits in neurobehavioural assessments including functional observational battery (decreased landing foot splay, decreased fore and hind limb grip strength that seemed to manifest later in age) and learning and memory (at ≥8 mg/kg/day, approximately 0.2 times the human exposure by AUC at the recommended dose), and decreased femur length (at ≥16 mg/kg/day, approximately 0.3 times the human exposure by AUC at the recommended dose) were observed.
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