Chemical formula: C₂₂H₁₉ClN₄O₅ Molecular mass: 454.863 g/mol PubChem compound: 9911830
Tivozanib potently and selectively blocks all 3 Vascular Endothelial Growth Factor receptors (VEGFR) and has been shown to block various VEGF-induced biochemical and biologic responses in vitro, including VEGF-ligand-induced phosphorylation of all three VEGFR 1, 2 and 3, and proliferation of human endothelial cells. The next most potently inhibited kinase is c-kit which is 8-fold less sensitive to inhibition by tivozanib compared to VEGFR 1, 2 and 3. VEGF is a potent mitogenic factor that plays a central role in angiogenesis and vascular permeability of tumour tissues. By blocking VEGF-induced VEGFR activation, tivozanib inhibits angiogenesis and vascular permeability in tumour tissues, leading to inhibition of tumour growth in vivo.
In a cardiac safety study of 50 patients with advanced solid tumours treated with tivozanib at 1340 microgram daily for 21 days, the mean change from baseline in QTcF was 6.8 ms on day 21 of dosing. The maximum change in QTcF from baseline was 9.3 ms (90% CI: 5, 13.6), which occurred 2.5 hours after dosing on Day 21. The central tendency change for all measured days and across all time points was 2.2 ms. No subjects had a new >500 ms change in QTcF; 2 patients (4%) had QTcF values >480 ms. One subject (2%) had a >60 ms change from baseline in QTcF and 6 subjects (12%) had a 30 ms to 60 ms change from baseline.
Following oral administration of tivozanib, peak serum levels are achieved after approximately 2 to 24 hours. After a single 1340 microgram dose, mean Cmax was 10.2 to 25.2 ng/mL across healthy subject and patient studies. Single dose AUC0-inf for healthy volunteers dosed with 1340 microgram tivozanib was 1,950 to 2,491 ng.hr/mL. After once daily dosing of 1340 microgram tivozanib for 21 or 28 days in RCC patients, Cmax was 67.5 to 94.3 ng/mL and AUC0-24 was 1,180 to 1,641 ng.hr/mL. Exposure is dose proportional between 890 and 1340 microgram and dose related over the wider range of 450 mg and 1790 microgram. Accumulation at steady-state is approximately 6- to 7- fold the exposure observed at single-dose levels. Clearance is similar between acute and chronic dosing indicating no time dependent changes in PK.
When tivozanib was evaluated in a food effect study in healthy subjects, a high fat meal decreased the peak serum concentrations (Cmax) by 23.4% compared to the fasted state. There was no effect of food on the overall exposure (AUC). Based on these data, tivozanib can be dosed with or without food.
In vitro protein binding studies have shown that tivozanib is >99% bound to plasma proteins. No concentration dependence of plasma protein binding was observed over the range of 0.1 to 5 μmol/L tivozanib. Albumin is the major tivozanib binding component in human plasma. In vitro studies have shown that tivozanib is neither a substrate nor an inhibitor of the multidrug efflux pump, P-glycoprotein. In vitro studies suggest that tivozanib is an inhibitor of intestinal BCRP.
In vitro metabolism studies have shown that CYP3A4 and CYP1A1 are capable of metabolising tivozanib. Unchanged tivozanib is the major circulating form of the molecule, and there were no major metabolites detected in serum at exposure equal to or greater than 10% of the total radioactivity exposure. As CYP1A1 is primarily expressed in extrahepatic tissues such as the lung and intestine, it was considered unlikely that this isoform would be extensively involved in hepatic metabolism.
In vitro studies have shown that metabolites of tivozanib can undergo UGT mediated biotransformation via the UGT1A1, UGT1A3, UGT1A7, UGT1A8, UGT1A9, and UGT1A10 pathways. Direct N-glucoronidation of tivozanib was a minor pathway of metabolism in vitro.
After chronic dosing of tivozanib in RCC patients for 21 days followed by 7 days without administration of tivozanib, tivozanib Cmin is approximately 16.0 to 30.9 ng/mL. In studies that evaluated the terminal elimination phase, tivozanib had a mean t1⁄2 of 4.5-5.1 days. After a single dose oral dose of [14C] tivozanib, approximately 79% of the radioactivity was recovered in the faeces and approximately 12% was found in the urine as metabolites. There was no unchanged tivozanib recovered in the urine indicating that tivozanib does not undergo renal excretion. [14C] Tivozanib was the predominant drug-related material in faeces. There were no [14C]-containing metabolites present in faeces at greater than 10% of the dose.
Based on the population pharmacokinetic analysis, there is no clinically relevant effect of age, gender or race on the pharmacokinetics of tivozanib. Hepatic impairment Results from a single dose study to evaluate the pharmacokinetics, safety and tolerability of tivozanib in subjects with hepatic impairment show that across the entire measurement period, tivozanib was eliminated more slowly in subjects with moderate (Child-Pugh Class B) or severe (Child-Pugh Class C) hepatic impairment. Tivozanib exposure was increased in patients with severe hepatic impairment (mean AUC0-∞ by 4.0-fold) and in patients with moderate hepatic impairment (mean AUC0-∞ by 2.6-fold). No significant increase in exposure was observed in patients with mild (Child-Pugh Class A) hepatic impairment (mean AUC0-∞ by 1.2-fold). Tivozanib should be used with caution in patients with moderate hepatic impairment and the dose reduced to one 1340 microgram capsule every other day. Tivozanib should not be used in patients with severe hepatic impairment.
Clinical studies with tivozanib were conducted in RCC patients with serum creatinine concentration ≤2 times the upper limit of normal, including those who may have had a prior nephrectomy. Although the impact of further impairment of renal function on the overall disposition of tivozanib is unknown, a clinical study has shown that no unchanged tivozanib is excreted in the urine indicating that tivozanib does not undergo renal excretion.. According to the population pharmacokinetic analysis of tivozanib exposure, no dose adjustment is required in patients with mild or moderate renal impairment. Experience of tivozanib use in patients with severe renal impairment is limited and caution is advised.
In vitro studies with tivozanib indicate that it is not a CYP enzyme inducer. In vitro studies conducted in human liver microsomes and hepatocytes evaluating the activity of CYP1A2, CYP2B6, CYP2A6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP3A4 suggested that tivozanib is a weak inhibitor of CYP2B6 and CYP2C8. Based on the in vitro IC 50 and in vivo unbound Cmax, tivozanib was unlikely to interact in a clinically relevant manner with active substances that are metabolised by these enzyme pathways.
Studies conducted in vitro have shown that tivozanib is not a potent inhibitor of UGT (UDP-glucuronosyltransferase) metabolic activities and clinically relevant drug-drug interactions are unlikely with medicinal products metabolised by these pathways.
In vitro studies have shown that tivozanib is neither a substrate nor inhibitor of the transporter proteins MDR1 (P-gp), OCT1, OATP1B1, OATP1B3 and BSEP. Furthermore, tivozanib was not an in vitro inhibitor of OAT1, OAT3, OCT2, MATE1 and MATE2-K or substrate of MRP2 and BCRP.
Tivozanib inhibits the transporter protein BCRP in vitro, at concentrations that are likely to restrict the effect to intestinal BCRP activity in vivo.
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.
In repeat-dose toxicity studies in rats, abnormalities were noted in growing incisors (thin brittle teeth, tooth loss, malocclusions) at doses approximately 2-fold greater than the calculated human equivalent dose and growth plate hypertrophy was observed at doses approximately 0.7- to 7-fold greater than the calculated human equivalent dose. Tivozanib was shown to cause growth plate hypertrophy, absence of active corpora lutea and no maturing follicles in cynomolgus monkeys at dose levels that produced exposures equivalent to those seen at the recommended clinical dose.
Tivozanib may impair human fertility. In nonclinical studies assessing mating and fertility parameters in male rats, doses >2-fold higher than the recommended clinical dose, produced increased epididymis and testis weights associated with infertility. Increased testis weights were observed at a dose 7-fold higher than the recommended clinical dose. In female rats, an increase in non-viable foetuses was noted at a dose 0.7-fold the recommended clinical dose, while dose levels ≥2 fold the recommended clinical dose produced infertility.
Tivozanib was shown to be teratogenic, embryotoxic and foetotoxic in pregnant rats at dose levels 5 times lower than the recommended clinical dose (based on a 60 kg human). Studies in pregnant rabbits showed no effect on maternal health or embryo foetal development at doses approximately 0.6 times the human exposure at the recommended dose.
Carcinogenicity studies have not been performed with tivozanib.
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