PubChem compound: 25161177
Tovorafenib is a central nervous system (CNS) penetrant, selective small molecule Type II RAF kinase inhibitor of mutant BRAF V600E, wild-type BRAF, and wild-type CRAF kinases, including RAF monomers and dimers and BRAF fusion, suppressing activation of the mitogen-activated protein kinase (MAPK) pathway.
At the recommended tovorafenib dose of 380 mg/m² orally once weekly (not to exceed 600 mg), a mean increase in the QT interval >20 milliseconds was not observed.
Tovorafenib pharmacokinetic parameters are presented as mean (CV%) unless otherwise indicated. Based on pop-PK modelling, tovorafenib steady state maximum concentration (Cmax) is 6.9 μg/ml (23%) and the area under the concentration-time curve (AUC) is 508 μg.h/ml (31%). Time to reach steady state of tovorafenib is 12 days (33%). Tovorafenib exposure increases in a dose-proportional manner. No clinically significant tovorafenib accumulation occurs.
Based on clinical study in healthy volunteers, tovorafenib median (minimum, maximum) time to achieve peak plasma concentration (Tmax) is 3 hours (1.5, 4 hours), following a single dose with tablets or oral suspension.
Based on clinical study in healthy volunteers, no clinically significant differences in tovorafenib Cmax and AUC were observed following administration of tablets with a high-fat meal (approximately 859 total calories, 54% fat) compared to fasted conditions, but the Tmax was delayed to 6.5 hours.
Based on pop-PK modelling, tovorafenib apparent volume of distribution is 60 L/m² (23%). Tovorafenib is 97.5% bound to human plasma proteins in vitro. Tovorafenib is highly protein-bound to albumin (≈95%) and moderately bound to alpha-1 acid glycoprotein (AAG) (≈42%).
Tovorafenib is primarily metabolised by aldehyde oxidase and CYP2C8 in vitro. CYP3A, CYP2C9 and CYP2C19 metabolise tovorafenib to a minor extent.
In vitro studies:
CYP450 enzymes: Tovorafenib inhibits CYP2C8, CYP2C9, CYP2C19 and CYP3A, but does not inhibit CYP1A2, CYP2B6 and CYP2D6 potentially at clinically relevant concentrations. Tovorafenib induces CYP3A, CYP2C8, CYP1A2, CYP2B6, CYP2C9 and CYP2C19 potentially at clinically relevant concentrations.
Transporter systems: Tovorafenib is not a substrate of breast cancer resistance protein (BCRP), P-glycoprotein (P-gp), OATP1B1 and OATP1B3. Tovorafenib has not been evaluated as a substrate of OAT1, OAT3, MATE1, MATE2-K and OCT2. Tovorafenib inhibits BCRP, OATP1B1, OATP1B3 and MATE1 potentially at clinically relevant concentrations.
Based on pop-PK modelling, tovorafenib terminal half-life is approximately 56 hours (33%) and the apparent clearance is 0.7 L/h/m² (31%). Based on clinical study in healthy volunteers, following a single oral dose of radiolabelled tovorafenib, 66.1% of the total radiolabelled dose was recovered in the faeces (8.6% unchanged) and 28.7% of the dose was recovered in the urine (0.2% unchanged).
Based on pop-PK modelling, no clinically significant differences in the pharmacokinetics of tovorafenib were observed based on age (range: 1 to 94 years). Cmax and AUC in paediatric patients aged 11 months to 17 years were within the range of values observed in adults given the same dose per body surface area.
Based on pop-PK modelling, no clinically significant differences of tovorafenib were observed in patients with mild-to-moderate renal impairment (eGFR ≥30 ml/min/1.73 m² calculated by Schwartz equation or MDRD equation). Tovorafenib has not been studied in patients with severe (eGFR <30 ml/min/1.73 m²) renal impairment.
Based on pop-PK modelling of PK data derived from clinical studies, no clinically significant differences of tovorafenib were observed in patients with mildly abnormal liver functions tests (defined as bilirubin ≤ upper limit of normal [ULN] and Aspartate Aminotransferase (AST) > ULN or bilirubin > 1 to 1.5x ULN and any AST). Tovorafenib has not been studied in patients with moderately abnormal liver functions tests (defined as bilirubin > 1.5x to 3x ULN and any AST) or severely abnormal liver functions tests (defined as total bilirubin > 3 x ULN and any AST).
No clinically significant differences in the pharmacokinetics of tovorafenib were observed based on race (White, Black, Asian).
No clinically significant differences in the pharmacokinetics of tovorafenib were observed based on sex.
Tovorafenib exposure is associated with reduction in height-for-age Z-scores in paediatric patients. Reduced height-for-age risk persists during treatment with tovorafenib. Higher tovorafenib exposure was associated with increased risk of adverse reactions such as skin rash and elevated liver enzymes (AST and ALT). The exposure-response relationship for overall response rate based on RAPNO-LGG was not clinically significant over the dose range of 290 to 476 mg/m² (0.76-1.25 times the recommended dose).
In vitro, tovorafenib increased phosphorylation of extracellular signal-regulated kinase (ERK) at clinically relevant concentrations in cells with neurofibromatosis Type 1loss of function (NF1-LOF) suggesting activation, rather than inhibition, of the MAP kinase pathway. In an NF1 genetically engineered mouse model of plexiform neurofibroma without BRAF alteration, tovorafenib did not have antitumour activity and while not statistically significant, an increase in tumour volume was noted in 2/12 mice (approximately 17%).
In hERG-transfected HEK293 cells, hERG channel was inhibited indicating potential for QT prolongation. Half-maximal inhibitory concentration was 8.9 μM which is 32-fold higher than the clinical plasma unbound concentration in adults.
Adverse reactions not observed in clinical studies, but seen in animals at exposure levels similar to clinical exposure levels and with possible relevance to clinical use were as follows: Tovorafenib was not carcinogenic in a 26-week (or 6-month) study in transgenic mice at exposures approximately 0.6-fold the human exposure (AUC) at the recommended human dose. Based on in vitro and in vivo studies, tovorafenib is not considered genotoxic at clinically relevant exposures. In a preliminary embryofetal development study in rats, total litter loss due to early resorptions was observed in all females at exposure levels lower than the recommended dose in human. This resulted in no foetus available for further examination, and explains the absence of further developmental studies (pivotal embryofetal development studies and prenatal and postnatal development study). In a fertility and early embryonic development study in female rats, tovorafenib decreased the number of pregnancies, corpora lutea, and live embryos, as well as increased post-implantation losses at doses as low as approximately 0.8-fold the human exposure at the recommended dose based on AUC.
In repeat-dose toxicology studies in rats of up to 3 months duration, tovorafenib-related findings in female rats included reversible increased thickness of the vaginal mucosa, increased size and/or numbers of corpora haemorrhagicum and haemorrhage, and non-reversible cystic follicles, decreased corpora lutea, and interstitial cell hyperplasia were observed in ovaries at doses approximately 0.4-fold the human exposure at the recommended dose based on AUC. In male rats, tovorafenib reduced weights of epididymis and testes, which correlated with reversible tubular degeneration/atrophy of the testes and reduced epididymal sperm at doses approximately 0.3-fold the human exposure at the recommended dose based on AUC.
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