Chemical formula: C₂₆H₂₇FN₁₀ Molecular mass: 498.57 g/mol PubChem compound: 118023034
Avapritinib is a Type 1 kinase inhibitor that has demonstrated biochemical in vitro activity on the PDGFRA D842V and KIT D816V mutants associated with resistance to imatinib, sunitinib and regorafenib with half maximal inhibitory concentrations (IC50) of 0.24 nM and 0.27 nM, respectively, and greater potency against clinically relevant KIT exon 11, KIT exon 11/17 and KIT exon 17 mutants than against the KIT wild-type enzyme.
In cellular assays, avapritinib inhibited the autophosphorylation of KIT D816V and PDGFRA D842V with IC50 of 4 nM and 30 nM, respectively. In cellular assays, avapritinib inhibited the proliferation in KIT mutant cell lines, including a murine mastocytoma cell line and a human mast cell leukaemia cell line. Avapritinib also showed growth inhibitory activity in a xenograft model of murine mastocytoma with KIT exon 17 mutation.
The ability of avapritinib to prolong the QT interval was assessed in 27 patients administered avapritinib at doses of 300/400 mg (1.33 times the 300 mg dose recommended for GIST patients, 12 to 16 times the 25 mg dose recommended for ISM patients) once daily in an open-label, single-arm study in patients with GIST. The estimated mean change from baseline in QTcF was 6.55 ms (90% confidence interval [CI]: 1.80 to 11.29) at the observed steady state geometric mean Cmax of 899 ng/mL (12.8-fold higher than the steady state geometric mean Cmax of avapritinib at 25 mg dose once daily in patients with ISM). No effect on heart rate or cardiac conduction (PR, QRS, and RR intervals) was observed.
Following administration of avapritinib once daily, steady state was reached by 15 days.
After a single dose and repeat dosing of avapritinib, systemic exposure of avapritinib was dose- proportional over the dose range of 30 to 400 mg once daily in patients with unresectable or metastatic GIST. The steady state geometric mean (CV%) maximum concentration (Cmax) and area under the concentration-time curve (AUC0-tau) of avapritinib at 300 mg once daily was 813 ng/mL (52%) and 15400 h•ng/mL (48%), respectively. The geometric mean accumulation ratio after repeat dosing was 3.1 to 4.6.
Steady-state Cmax and AUC of avapritinib increased proportionally over the dose range of 30 mg to 400 mg once daily in patients with AdvSM. The steady state geometric mean (CV%) Cmax and AUC0-24 of avapritinib at 200 mg once daily was 377 ng/mL (62%) and 6600 h•ng/mL (54%), respectively. The geometric mean accumulation ratio after repeat dosing (30-400 mg) was 2.6 to 5.8.
The Cmax and AUC of avapritinib increased proportionally over the dose range of 25 mg to 100 mg once daily in patients with ISM. The steady state geometric mean (CV%) Cmax and AUC0-24 of avapritinib at 25 mg once daily was 70.2 ng/mL (47.8%) and 1330 h•ng/mL (49.5%), respectively. The geometric mean accumulation ratio after repeat dosing was 3.59.
Following administration of single oral doses of avapritinib of 25 to 400 mg, the median time to peak concentration (Tmax) ranged from 2 to 4 hours postdose. The absolute bioavailability has not been determined. The population estimated mean oral bioavailability of avapritinib in patients with GIST and AdvSM is 16% and 47% lower, respectively, compared to that in patients with ISM.
Avapritinib Cmax and AUCinf were increased by 59% and 29%, respectively, in healthy subjects administered avapritinib after a high fat meal (approximately 909 calories, 58 grams carbohydrate, 56 grams fat and 43 grams protein) compared to the Cmax and AUCinf after overnight fasting.
Avapritinib is 98.8% bound to human plasma proteins in vitro and the binding is not concentration-dependent. The blood-to-plasma ratio is 0.95. Population estimated apparent central volume of distribution of avapritinib (Vc/F) is 971 L at median lean body weight of 54 kg. The inter-individual variability of Vc/F is 50.1%.
In vitro studies demonstrated that oxidative metabolism of avapritinib is predominantly mediated by CYP3A4, CYP3A5 and to a minor extent by CYP2C9. The relative contributions of CYP2C9 and CYP3A to the in vitro metabolism of avapritinib were 15.1% and 84.9%, respectively. The formation of the glucuronide M690 is catalysed mainly by UGT1A3.
Following a single dose of approximately 310 mg (~100 μCi) [14C]avapritinib to healthy subjects, oxidation, glucuronidation, oxidative deamination and N-dealkylation were the primary metabolic pathways. Unchanged avapritinib (49%) and metabolites, M690 (hydroxy glucuronide; 35%) and M499 (oxidative deamination; 14%) were the major circulating radioactive components. Following oral administration of avapritinib 300 mg once daily in patients, the steady state AUC of the constitutive enantiomers of M499, BLU111207 and BLU111208 are approximately 35% and 42% of the AUC of avapritinib. At a dose of 25 mg once daily, the metabolite to parent ratio for BLU111207 and BLU111208 was 10.3% and 17.5% respectively. Compared to avapritinib (IC50 = 4 nM), the enantiomers BLU111207 (IC50 = 41.8 nM) and BLU111208 (IC50 = 12.4 nM) are 10.5- and 3.1-fold less potent, respectively, against KIT D816V in vitro.
In vitro studies demonstrated that avapritinib is a direct inhibitor of CYP3A4 and a time-dependent inhibitor of CYP3A4, at clinically relevant concentrations. In vitro, avapritinib did not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP2D6 at clinically relevant concentrations.
In vitro, at clinically relevant concentrations, avapritinib induced CYP3A. In vitro, avapritinib did not induce CYP1A2 or CYP2B6 at clinically relevant concentrations.
Following single doses of avapritinib in patients with GIST, AdvSM and ISM, the mean plasma elimination half-life of avapritinib was 32 to 57 hours, 20 to 39 hours and 38 to 45 hours, respectively.
Population estimated mean apparent clearance (CL/F) of avapritinib is 16.9 L/h. In AdvSM patients, time-dependent CL/F on Day 9 was reduced to 39.4% compared to GIST and ISM patients. The inter-individual variability in CL/F is 44.4%.
Following a single oral dose of approximately 310 mg (~100 μCi) [14C]avapritinib to healthy subjects, 70% of the radioactive dose was recovered in faeces and 18% excreted in urine. Unchanged avapritinib accounted for 11% and 0.23% of the administered radioactive dose excreted in faeces and urine, respectively.
In vitro, avapritinib is not a substrate of P-gp, BCRP, OAT1, OAT3, OCT1, OCT2, OATP1B1, OATP1B3, MATE1, MATE2-K and BSEP at clinically relevant concentrations.
Avapritinib is an inhibitor of P-gp, BCRP, MATE1, MATE2-K, and BSEP in vitro. In vitro, avapritinib did not inhibit OATP1B1, OATP1B3, OAT1, OAT3, OCT1, or OCT2 at clinically relevant concentrations.
No clinical drug-drug interaction studies have been conducted. Based on both population and noncompartmental pharmacokinetic analyses, the effect of gastric acid reducing agents on the bioavailability of avapritinib is not clinically relevant.
Population pharmacokinetic analyses indicate that age (18-90 years), body weight (40-156 kg), sex and albumin concentration have no effect on the exposure of avapritinib. Concomitant use of proton pump inhibitors (PPI) on bioavailability (F) and lean body weight on the apparent central volume of distribution (Vc/F) were identified as statistically significant covariates with impact on avapritinib exposure. Lean body weight (30 kg to 80 kg) showed modest impact on Cmax at steady state (+/- 5%), while concomitant use of PPIs led to ~19% reduction in AUC and Cmax. These minor effects on exposure are not clinically significant given the PK variability (>40% CV) and are not expected to impact efficacy or safety. No significant effect of race on the pharmacokinetics of avapritinib was found, although the low number of Black (N=27) and Asian (N=26) subjects limits the conclusions that can be derived based on race.
As hepatic elimination is a major route of excretion for avapritinib, hepatic impairment may result in increased plasma avapritinib concentrations. Based on a population pharmacokinetic analysis, avapritinib exposures were similar between 72 subjects with mild hepatic impairment (total bilirubin within upper limit of normal [ULN] and AST > ULN or total bilirubin >1 to 1.5 times ULN and any AST), 13 subjects with moderate hepatic impairment (total bilirubin >1.5 to 3.0 times ULN and any AST), and 402 subjects with normal hepatic function (total bilirubin and AST within ULN). In a clinical study investigating the effect of severe hepatic impairment on the pharmacokinetics of avapritinib following administration of a single oral dose of 100 mg avapritinib, the mean unbound AUC was 61% higher in subjects with severe hepatic impairment (Child-Pugh Class C) as compared to matched healthy subjects with normal hepatic function. A lower starting dose is recommended in patients with severe hepatic impairment.
Based on a population pharmacokinetic analysis, avapritinib exposures were similar among 136 subjects with mild renal impairment (CLcr 60-89 mL/min), 52 subjects with moderate renal impairment (CLcr 30-59 mL/min) and 298 subjects with normal renal function (CLcr ≥90 mL/min), suggesting that no dose adjustment is necessary in patients with mild to moderate renal impairment. The pharmacokinetics of avapritinib in patients with severe renal impairment (CLcr 15-29 mL/min) or end-stage renal disease (CLcr <15 mL/min) has not been studied.
Haemorrhage in the brain and spinal cord occurred in dogs at doses greater than or equal to 15 mg/kg/day (approximately 9.0, 1.8 and 0.8 times the human exposure based on AUC at 25 mg, 200 mg and 300 mg dose once daily, respectively) and choroid plexus oedema in the brain occurred in dogs at doses greater than or equal to 7.5 mg/kg/day (approximately 4.7, 1.0 and 0.4 times the human exposure based on AUC at the clinical dose of 25 mg, 200 mg and 300 mg once daily, respectively). Rats manifested convulsions, which was potentially secondary to inhibition of Nav 1.2 at systemic exposures ≥96, 12 and ≥8-fold higher than the exposure in patients at the clinical dose of 25 mg, 200 mg and 300 mg once daily.
In a 6 month repeat dose toxicology study in rats, rats manifested haemorrhagic and cystic degeneration of the ovarian corpus lutea and vaginal mucification at dose levels greater or equal to 3 mg/kg/day with exposure margins of 15, 3 and 1.3 times the human exposure based on AUC at 25 mg, 200 mg and 300 mg, respectively. In a 9 month repeat dose toxicology study in dogs, hypospermatogenesis (¾ males) was observed at the highest dose tested, 5 mg/kg/day (5.7, 1.2 and <1 times the human exposure (AUC) at 25 mg, 200 mg and 300 mg dose, respectively).
Avapritinib was not mutagenic in vitro in the bacterial reverse mutation assay (Ames test). It was positive in the in vitro chromosome aberration test in cultured human peripheral blood lymphocytes but negative in the rats for both the bone marrow micronucleus test and for the chromosomal damage liver comet assays, and thus, overall non-genotoxic. The carcinogenic potential of avapritinib was evaluated in a 6 month transgenic mouse study where higher incidences of lower thymic cortical cellularity were noted at 10 and 20 mg/kg/day doses. A long-term carcinogenicity study with avapritinib is ongoing.
A dedicated combined male and female fertility and early embryonic development study was conducted in rats at oral avapritinib doses of 3, 10, and 30 mg/kg/day for males, and 3, 10, and 20 mg/kg/day for females. No direct effects on male or female fertility were noted at the highest dose levels tested in this study (100.8 and 62.6 times the human exposure (AUC) at 25 mg, 20.3 and 9.5 times the human exposure (AUC) at 200 mg and 8.7 and 4.1 times the human exposure (AUC) at 300 mg).
Avapritinib partitioned into seminal fluids up to 0.1 times the concentration found in human plasma at 25 mg. There was an increase in pre-implantation loss and in early resorptions with exposure margins of 15, 3 and 1.3 times the human exposure (AUC) at the clinical doses of 25 mg, 200 mg and 300 mg, respectively. Reduction in sperm production and relative testicular weight were observed in male rats administered avapritinib at exposures of 7 and 30 times, 1 and 5 times, and 0.6 and 3 times the 25 mg, 200 mg, and 300 mg human doses, respectively.
In an embryo-foetal development toxicity study in rats, avapritinib showed embryotoxic and teratogenic effects (decreases in foetal weights and viability, and increases in visceral and skeletal malformations). Oral administration of avapritinib during the period of organogenesis was teratogenic and embryotoxic in rats at exposures approximately 31.4, 6.3 and 2.7 times the human exposure (AUC) at the 25 mg, 200 mg, and 300 mg dose, respectively.
An in vitro phototoxicity study in 3T3 mouse fibroblasts as well as a phototoxicity study in pigmented rats demonstrated that avapritinib has a slight potential for phototoxicity.
© All content on this website, including data entry, data processing, decision support tools, "RxReasoner" logo and graphics, is the intellectual property of RxReasoner and is protected by copyright laws. Unauthorized reproduction or distribution of any part of this content without explicit written permission from RxReasoner is strictly prohibited. Any third-party content used on this site is acknowledged and utilized under fair use principles.