Tisotumab vedotin is an antibody-drug conjugate (ADC) directed to tissue factor (TF), a cell surface protein expressed at elevated levels on a variety of solid tumours relative to normal tissue. The small molecule, MMAE, is a microtubule-disrupting agent, attached to the antibody via a protease-cleavable linker. Tisotumab vedotin binds to TF-expressing tumour cells, the ADC-TF complex is internalised, and local release of MMAE occurs via proteolytic cleavage. MMAE disrupts the microtubule network of actively dividing cells, leading to cell cycle arrest and apoptotic cell death.
Direct cytotoxicity in TF-expressing cells, bystander cytotoxicity, antibody-dependent cellular cytotoxicity, antibody-dependent cellular phagocytosis, and immunogenic cell death has been demonstrated in vitro with tisotumab and/or tisotumab vedotin.
Anti-drug antibodies (ADA) were commonly detected (5% across clinical studies). No evidence of ADA impact on pharmacokinetics, efficacy or safety was observed, however, data are still limited.
The effect of tisotumab vedotin (2 mg/kg every 3 weeks) on the QTc interval was evaluated in 153 patients. At the dose of 2 mg/kg every 3 weeks, tisotumab vedotin had no clinically meaningful effect on QTc prolongation.
Based on population pharmacokinetic analysis tisotumab vedotin central volume of distribution was estimated to be 3.10 L.
In vitro, the binding of MMAE to human plasma proteins ranged from 68–82%.
Tisotumab vedotin catabolism has not been studied in humans; however, it is expected to undergo catabolism to small peptides, amino acids, unconjugated MMAE, and unconjugated MMAE-related metabolites. Tisotumab vedotin releases MMAE via proteolytic cleavage, and MMAE is primarily metabolised by CYP3A4 in vitro. In vivo data in animals and humans suggest that only a small fraction of MMAE released from tisotumab vedotin is metabolised. The levels of MMAE metabolites have not been measured in human plasma.
Based on population pharmacokinetic analysis, the median terminal half-life of tisotumab vedotin is approximately 4.04 days and the terminal half-life of MMAE is approximately 2.56 days. The linear clearance of tisotumab vedotin was estimated to be 1.42 L/day and following a 2 mg/kg dose approximately 60% of the dose was estimated to be eliminated by linear clearance (CL). Clearance of unconjugated MMAE was estimated to be 42.8 L/day. Elimination of MMAE appeared to be limited by its rate of release from tisotumab vedotin.
The excretion of tisotumab vedotin is not fully characterised. Following a single dose of another ADC that contains MMAE, 17% of the total MMAE administered was recovered in faeces and 6% in urine over a 1-week period, primarily as unchanged drug. A similar excretion profile of MMAE is expected after tisotumab vedotin administration.
Based on population pharmacokinetic analysis, age (21 to 81 years) does not have a clinically meaningful effect on the pharmacokinetics of tisotumab vedotin.
Based on population pharmacokinetic analysis, gender does not have a clinically meaningful effect on the pharmacokinetics of tisotumab vedotin.
Based on population pharmacokinetic analysis, no clinically meaningful differences in exposures of tisotumab vedotin and MMAE were observed in patients with mild (creatinine clearance; CrCL >60-90 mL/min, n=142) or moderate (CrCL 30-60 mL/min, n=42) renal impairment compared to patients with normal renal function. The effect of severe renal impairment or end-stage renal disease with or without dialysis on tisotumab vedotin and unconjugated MMAE pharmacokinetics is unknown.
Based on population pharmacokinetic analysis, no clinically meaningful differences in exposures of tisotumab vedotin were observed in patients with mild hepatic impairment (total bilirubin >1 to 1.5 × ULN and any AST, or total bilirubin ≤ ULN and AST > ULN, n=58) compared to patients with normal hepatic function, while MMAE exposures were 37% higher in mild hepatic impairment as compared to normal hepatic function. The effect of moderate or severe hepatic impairment or liver transplantation on the pharmacokinetics of tisotumab vedotin or unconjugated MMAE is unknown.
In an exposure-response analysis at 2 mg/kg every 3 weeks, a higher tisotumab vedotin exposure was associated with higher incidence of some adverse reactions (e.g., Grade ≥2 ocular adverse reactions) and a lower exposure was associated with lower efficacy.
Repeat-dose toxicity studies were performed with tisotumab vedotin at approximately 2.3-4.3 times the human area under the curve (AUC) at the recommended clinical dose. Skin lesions were noted in a repeat-dose study at ≥3 mg/kg in monkeys (13 weeks). The skin changes were fully reversible by the end of a 6-week recovery period. In both rats and cynomolgus monkeys, administration of MMAE and tisotumab vedotin (only monkeys dosed at ≥3 mg/kg) led to reversible bone marrow toxicity and associated peripheral blood cell effects. Reddened or swollen eyes and conjunctiva (with or without discharge), and/or conjunctivitis was observed following tisotumab vedotin treatment in monkeys at 5 mg/kg (13 weeks). These findings reversed following a 6-week recovery period.
Carcinogenicity studies in animals have not been performed with tisotumab vedotin or MMAE.
MMAE was positive for genotoxicity in the in vivo rat bone marrow micronucleus study through an aneugenic mechanism.
Dedicated fertility studies in animals have not been performed with tisotumab vedotin or MMAE. However, results of repeat-dose toxicity studies indicate the potential for tisotumab vedotin to impair male and female fertility.
Results of a 13-week repeat-dose toxicity study in cynomolgus monkeys administered tisotumab vedotin demonstrated seminiferous tubular atrophy of the testes and absence of sperm, decreased sperm content, and epithelial vacuolation in the epididymides. The changes were associated with decreased testicular size, and reduced or total absence of sperm counts and sperm motility was observed at doses of 1, 3, and 5 mg/kg corresponding to approximately 0.5- to 4-fold the human systemic exposure (based on AUC) at the clinically recommended dose. There was partial recovery of the testes and epididymides findings at 3 and 5 mg/kg; and full recovery at 1 mg/kg after a 6-week postdose period.
Ovarian effects were observed in repeat-dose toxicity studies of other MMAE-containing ADCs. A mild to moderate decrease in, or absence of, secondary and tertiary ovarian follicles was observed in young female cynomolgus monkeys at doses ≥ 3 mg/kg weekly for 4 weeks. These effects showed evidence of recovery 6 weeks after the end of dosing and no changes were observed in primordial follicles.
Animal reproduction studies have not been conducted with tisotumab vedotin to evaluate its effect on reproduction and foetal development. Based on its mechanism of action and findings from animal studies, tisotumab vedotin could cause embryo-foetal harm when administered to a pregnant woman. Intravenous administration of MMAE to pregnant rats during organogenesis (gestational Days 6 and 13) resulted in increased total resorptions, post implantation loss, early delivery, loss of viable foetuses, and teratogenic embryo-foetal toxicity at a dose of 0.2 mg/kg (approximately 0.5 times the human AUC at the recommended dose).
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