Chemical formula: C₂₃H₂₅N₇O₂ Molecular mass: 431.207 g/mol PubChem compound: 86267612
Vimseltinib is a selective small molecule tyrosine kinase inhibitor that targets colony stimulating factor 1 receptor (CSF1R). The CSF1/CSF1R signalling axis has a critical role in the development of TGCT. In vitro enzyme and cell-based assays have shown that vimseltinib inhibited CSF1R autophosphorylation and signalling induced by CSF1 ligand binding, as well as cellular function and proliferation of cells expressing CSF1R. Vimseltinib also inhibited CSF1R expressing cells and blocked downstream signalling in preclinical models in vivo.
Vimseltinib exerts its anti-tumour effects via depletion of CSF1R-dependent macrophages and inflammatory cells.
A decline in the number of hepatic Kupffer cells due to CSF1R inhibition leads to decreased clearance of serum enzymes, including AST, ALT, and CPK. This results in an increase in the serum levels of these enzymes.
Positive exposure-response relationships were observed between vimseltinib exposure and all grades of oedema, pruritus, rash, and increases of AST ALT, CPK and creatinine.
Vimseltinib reaches peak plasma concentrations at a median of 1 hour after oral administration of single 30 mg dose of vimseltinib under fasted conditions. Vimseltinib pharmacokinetic (PK) parameters estimated by population PK (popPK) model and provided as geometric mean (coefficient of variation [%]; CV%), were determined following a single oral dose of 30 mg or at steady state following multiple doses of 30 mg twice weekly in TGCT patients. Vimseltinib Cmax is 283 ng/mL (36%) or 747 ng/mL (39%) after a 30 mg single dose or at steady state, respectively, AUC0-inf is 46.9 μg*h/mL (45%) after a single dose and AUC0-24h is 13.4 μg*h/mL (45%) at steady state. Steady state plasma concentrations were similar in patients and healthy volunteers and were achieved after approximately 5 weeks with an accumulation ratio of 2.6.
No clinically significant differences in vimseltinib pharmacokinetics were observed following administration of a high-fat meal, compared to fasted conditions.
The geometric mean (CV%) apparent volume of distribution (Vz/F) of vimseltinib is 90 L (16%). Vimseltinib is 96.5% bound to human plasma proteins in vitro.
Vimseltinib has no major circulating metabolite. Primary metabolism occurred by oxidation, N-demethylation, and N-dealkylation; secondary biotransformation pathways included N-demethylation, dehydrogenation and oxidation.
CYPs are not anticipated to play a major role in vimseltinib's metabolism.
The geometric mean (geometric CV%) apparent clearance (CL/F) of vimseltinib is 0.5 L/h (23%) with an elimination half-life of approximately 6 days following single-dose administration.
Approximately 43% of the dose was recovered in faeces (9.1% unchanged) and 38% in urine (5.1% unchanged) after a single oral radiolabelled dose.
Vimseltinib pharmacokinetics are dose proportional.
No clinically relevant differences in the pharmacokinetics of vimseltinib were observed based on age (20 to 91 years), sex, race (Asian, Black or African American, White) and body weight (43 to 150 kg).
Based on a popPK analysis, no significant differences in the pharmacokinetics of vimseltinib were observed in subjects with mild renal impairment (eGFR ≥60 mL/min) compared to subjects with normal renal function. Based on limited data, popPK estimated 8% and 27% higher Cmax,ss and Cavg,ss in patients with moderate renal impairment, respectively, but this increase in exposure is not considered clinically relevant. No clinical data are available in patients with severe renal impairment.
In subjects with mild hepatic impairment (Child-Pugh A), AUCinf was 24% lower and Cmax was 41.5% lower than in matched healthy participants. This reduction in exposure is not considered clinically relevant. PopPK and Pharmacokinetics/Pharmacodynamics (PKPD) modelling estimated that a dose reduction to 14 mg twice weekly in patients with mild hepatic impairment may result in reduced response. No clinical data are available. The effect of moderate to severe hepatic impairment (Child-Pugh B and C) on vimseltinib pharmacokinetics is unknown.
PopPK and PKPD modelling estimated that a dose reduction to 14 mg twice weekly in patients with a body weight of ≥115 kg may result in reduced response. No clinical data are available.
In vitro data in human hepatocytes showed that vimseltinib caused a concentration-dependent reduction of CYP1A2 mRNA expression by >50%, suggesting a down-regulation phenomenon. The clinical relevance of this finding is currently unknown.
Vimseltinib was not carcinogenic in an oral 6-month transgenic mouse carcinogenicity study at systemic exposures up to 7.6-times the vimseltinib exposure at the recommended human dose based on AUC.
In a 2-year oral rat carcinogenicity study, 2 out of 60 high dose males were identified as having histomorphologically different sarcomas in the synovium of the femorotibial joint at exposures approximately <1 and 1.4 times (unbound and total, respectively) the recommended human dose based on AUC. Both were classified as sarcoma, not otherwise specified. The relevance of this finding to humans is unknown but considering all available clinical and nonclinical data the carcinogenic risk after vimseltinib administration is considered low.
Vimseltinib toxicity was observed in a fertility and early embryonic development study in female rats at approximately 1.6-times the unbound vimseltinib exposure at the recommended human dose based on AUC. Post-implantation loss and increased uterine weights were observed at approximately 6-times the unbound vimseltinib exposure at the recommended human dose based on AUC. There were no treatment-related effects on mating, fertility, or pregnancy indices, and estrous cycles at any dose level tested. Male rats had lower epididymal and testes weights at approximately 3.6-times the unbound vimseltinib exposure at the recommended human dose based on AUC and there were no treatment-related effects on mating, fertility, or sperm parameters at any dose tested.
Administration of vimseltinib in rats resulted in foetal abnormalities of the cardiovascular (malformations) and skeletal (variations) systems, as well as additional indications of developmental toxicity, at a maternal exposure approximately 7- and 0.9-times the unbound vimseltinib exposure at the recommended human dose based on AUC.
In the pre- and postnatal developmental toxicity study, maternal mortality, total litter losses, reduced fetal body weights, and lower mean pup survival were observed at approximately 1.7-times the unbound vimseltinib exposure at the recommended human dose based on AUC. Total litter loss was also reported in groups treated at doses corresponding to unbound vimseltinib exposures lower than those at the recommended human dose.
In a 26-week repeat-dose toxicity study, recovery male rats that were administered 2.5 or 5 mg/kg/day had moderate to marked reductions in sperm and marked testicular atrophy (1 of 5 and 2 of 5 animals, respectively) corresponding to approximately 1.8 and 3.6-times the unbound vimseltinib exposure at the recommended human dose based on AUC, respectively. In a 39-week repeat-dose toxicity study, minimal to moderate epididymal mineralisation occurred in male dogs administered ≥4 mg/kg/day corresponding to exposures lower than the exposure at the recommended human dose based on AUC.
In repeat-dose toxicity studies of up to 26 weeks in rats, there were findings of swollen head and/or limbs, and abnormal teeth at doses of 1 mg/kg/day (approximately 0.96-times the unbound vimseltinib exposure at the recommended human dose based on AUC). The dental effects at doses of 5 mg/kg/day in male rats were associated with lower food consumption and reduced body weight. Chronic progressive nephropathy occurred in animals receiving ≥2.5 mg/kg/day (approximately ≥1.8-times the unbound vimseltinib exposure at the recommended human dose based on AUC). Degeneration of blood vessels in multiple tissues and increased physis thickness was observed in rats receiving 5 mg/kg/day (approximately 4-times the unbound vimseltinib exposure at the recommended human dose based on AUC).
Low recovery of total radioactivity in mass balance studies and slow elimination of vimseltinib are indicative of potential tissue accumulation. In a rat distribution study, prolonged retention of vimseltinib in eye uveal tract, eye(s), eye vitreous humor, and meninges due to melanin binding was observed. No CNS effects were noted in dogs up to the highest tested dose of 8 mg/kg corresponding to exposure below the anticipated clinical exposure at the recommended human dose. Therefore, clinical relevance of potential accumulation of vimseltinib in meninges remains unknown. Periocular swelling and epiphora observed in dogs at 8 mg/kg at exposures below the expected exposure in humans may be related to prolonged retention of vimseltinib in ocular tissues.
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