Molecular mass: 510.367 g/mol
Ripretinib is a novel tyrosine kinase inhibitor that inhibits KIT proto-oncogene receptor tyrosine kinase and PDGFRA kinase, including wild type, primary, and secondary mutations. Ripretinib also inhibits other kinases in vitro, such as PDGFRB, TIE2, VEGFR2, and BRAF.
Ripretinib exposure-response relationships and the time course of pharmacodynamics have not been fully characterized.
No large mean increase in QTc interval (i.e. >20 ms) was detected following treatment with ripretinib at the recommended dose of 150 mg taken orally once daily.
Ripretinib reaches peak plasma concentrations at a median of 4 hours after oral administration of single dose ripretinib 150 mg (given as three tablets each containing 50 mg). The mean (CV%) AUC0-∞ after a single dose of 150 mg of ripretinib was 9,856 (39%) and 8,146 (56%) ng•h/mL for ripretinib and DP-5439, respectively.
Administration with a high-fat meal increased ripretinib AUC0-24 and Cmax by 30% and 22%, respectively. DP-5439 AUC0-24 and Cmax were higher by 47% and 66%, respectively.
Both ripretinib and its active metabolite DP-5439 bind to plasma proteins at ≥99%. The mean (CV%) apparent volume of distribution (Vss/F) is approximately 302 (35%) L for ripretinib and 491 (38%) L for DP-5439.
CYP3A4/5 is the major metaboliser of ripretinib and its active metabolite DP-5439, while CYP2C8 and CYP2D6 are minor metabolisers.
Following oral administration of single dose ripretinib 150 mg in humans, mean (CV%) apparent oral clearance (CL/F) was 15.2 (39%) and 17.9 (56%) L/hr for ripretinib and DP-5439, respectively. Mean (CV%) half-life (t½) was 12.6 (17%) and 15.6 (23%) hours for ripretinib and DP-5439, respectively.
Systemic elimination of ripretinib was not primarily attributed to the kidney with 0.02% and 0.1% of the ripretinib dose excreted as ripretinib and DP-5439, respectively, in urine and 34% and 6% of the ripretinib dose excreted as ripretinib and DP-5439, respectively, in faeces.
Across the dose range of 20-250 mg, ripretinib and DP-5439 PK appeared to be less than dose proportional, especially at ripretinib doses higher than 150 mg.
Steady-state conditions are achieved within 14 days.
No clinically significant differences in the pharmacokinetics of ripretinib were observed based on age (19 to 87 years), sex, race (White, Black, and Asian), body weight (39 to 138 kg), and tumour (GIST or other solid tumours).
In clinical studies, no relevant differences in exposure were observed between patients with mild and moderate renal impairment (CLcr 30 to 89 mL/min estimated by Cockcroft-Gault) and patients with normal renal function. Based on a population pharmacokinetic analysis, no dose adjustment is recommended in patients with mild and moderate renal impairment. The pharmacokinetics and safety of ripretinib in patients with severe renal impairment (CLcr 15 to 29 mL/min estimated by Cockcroft-Gault) is limited. No dosing recommendation can be made in patients with severe renal impairment.
In clinical studies, no relevant differences in exposure were observed between patients with mild (total bilirubin ≤ upper limit of normal (ULN) and AST > ULN, or total bilirubin > ULN to ≤1.5 × ULN and any AST) hepatic impairment and normal hepatic function. Based on a population pharmacokinetic analysis, no dose adjustment is recommended in patients with mild hepatic impairment. The pharmacokinetics and safety of ripretinib in patients with moderate or severe hepatic impairment have not been studied; no dosing recommendation can be made in this subgroup.
The preclinical safety profile of ripretinib was assessed in rats and dogs for up to 13 weeks duration. Inflammation responses correlated with skin changes (discoloured, lesions) were recorded in rats (approximately 1.12 times the human exposure at 150 mg once daily). Elevated hepatic enzyme activity was reported in both species (approximately 1.12 and 1.3 times the human exposure at 150 mg once daily for rats and dogs, respectively). Dogs presented gastrointestinal effects (emesis and/or abnormal faeces) (approximately 1.3 times the human exposure at 150 mg once daily), and inflammatory responses illustrated by adverse skin lesions (approximately 0.14 times the human exposure at 150 mg once daily).
Carcinogenicity studies have not been conducted with ripretinib.
Ripretinib was found to be positive in an in vitro micronucleus assay. Ripretinib was not mutagenic in in vitro bacterial reverse mutation (Ames) assay nor in an in vivo rat bone marrow micronucleus assay, demonstrating the absence of significant genotoxic risk.
Dedicated fertility studies in male and female animals were not conducted with ripretinib. However, in a 13-week repeat-dose toxicity study in male rats, there were findings of degeneration in the seminiferous epithelium of the testes, and cellular debris of the epididymis in males administered 30 or 300 mg/kg/day but were considered of sufficient severity to affect reproduction at dose 300 mg/kg/day only (approximately 1.4 times the human exposure at 150 mg once daily).
In a pivotal embryofoetal development study, ripretinib was teratogenic in rats, inducing dose-related malformations primarily associated with the visceral and skeletal systems at a maternal dose of 20 mg/kg/day (approximately 1.0 times the human exposure at 150 mg once daily). Additionally, skeletal variations were already observed at 5 mg/kg/day. The developmental NOAEL for ripretinib was therefore established at 1 mg/kg/day (approximately 0.02 times the human exposure at 150 mg once daily).
A study investigating effects of ripretinib on the pre-/postnatal development was not performed.
Ripretinib indicates a potential for photoirritation/phototoxicity based on absorption in the UV visible range (above 290 nm). In vitro phototoxicity assessment in 3T3 mouse fibroblast cells suggest that ripretinib exhibits a potential for phototoxicity at clinically relevant concentrations following exposure to UVA and UVB radiation.
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