Tisotumab vedotin-tftv is a tissue factor (TF)-directed antibody drug conjugate (ADC). The antibody is a human IgG1 directed against cell surface TF. TF is the primary initiator of the extrinsic blood coagulation cascade. The small molecule, MMAE, is a microtubule-disrupting agent, attached to the antibody via a protease-cleavable linker. Nonclinical data suggests that the anticancer activity of tisotumab vedotin-tftv is due to the binding of the ADC to TF expressing cancer cells, followed by internalization of the ADC-TF complex, and release of MMAE via proteolytic cleavage. MMAE disrupts the microtubule network of actively dividing cells, leading to cell cycle arrest and apoptotic cell death. In vitro, tisotumab vedotin-tftv also mediates antibody-dependent cellular phagocytosis and antibody-dependent cellular cytotoxicity.
Tisotumab vedotin-tftv exposure-response relationships and the time course of pharmacodynamics response have not been fully characterized.
Cardiac Electrophysiology
At the recommended dose, tisotumab vedotin-tftv had no large mean effect on QTc prolongation (>20 msec).
Table 8 summarizes the exposure parameters of tisotumab vedotin-tftv and unconjugated MMAE (the cytotoxic component of tisotumab vedotin-tftv) following administration of one 3-week cycle of tisotumab vedotin-tftv 2 mg/kg to patients. Tisotumab vedotin-tftv concentrations peaked near the end of the infusion, while unconjugated MMAE concentrations peaked approximately 2 to 3 days after tisotumab vedotin-tftv dosing. Tisotumab vedotin-tftv Cmax increased proportionally, while AUC0-last increased in a more than dose-proportional manner, after a single dose ranging from 0.3–2.2 mg/kg (0.15 to 1.1 times the approved recommended dose). There was no accumulation of tisotumab vedotin-tftv and unconjugated MMAE. Steady-state concentrations of tisotumab vedotin-tftv and unconjugated MMAE were reached after 1 treatment cycle.
| Cmax=maximum concentration, AUC = area under the concentration-time curve from time 0 to 21 days (3 weeks) | ||
| Tisotumab Vedotin-tftv | Unconjugated MMAE |
Cmax | 40.8 (8.12) μg/mL | 5.91 (4.2) ng/mL |
AUC | 57.5 (13.4) day*μg/mL | 50 (35.8) day*ng/mL |
Distribution
The tisotumab vedotin-tftv steady state volume of distribution is 7.83 (%CV: 19.1) L. Plasma protein binding of MMAE ranged from 68% to 82%, in vitro.
Elimination
The median terminal half-life of tisotumab vedotin-tftv and unconjugated MMAE is 4.04 (range: 2.26-7.25) days and 2.56 (range: 1.81-4.10) days, respectively. The linear clearance of tisotumab vedotin-tftv and unconjugated MMAE was 1.54 (%CV: 28.8) L/day and 45.9 (%CV: 61.1) L/day, respectively. Elimination of MMAE appeared to be limited by its rate of release from tisotumab vedotin-tftv.
Metabolism
Tisotumab vedotin-tftv is expected to undergo catabolism to small peptides, amino acids, unconjugated MMAE, and unconjugated MMAE-related catabolites. Tisotumab vedotin-tftv releases unconjugated MMAE via proteolytic cleavage, and unconjugated MMAE is primarily metabolized by CYP3A4 in vitro.
Excretion
The excretion of tisotumab vedotin-tftv is not fully characterized. Following a single-dose of another ADC that contains MMAE, 17% of the total MMAE administered was recovered in feces and 6% in urine over a 1-week period, primarily as unchanged drug. A similar excretion profile of MMAE is expected after tisotumab vedotin-tftv administration.
Specific Populations
No clinically significant differences in the pharmacokinetics of tisotumab vedotin-tftv were observed based on age (21 to 81 years), sex, race (white vs non-white) or ethnicity (Hispanic or Latino vs non-Hispanic or non-Latino). No clinically significant differences in exposures of tisotumab vedotin-tftv and unconjugated MMAE were observed in patients with mild to moderate renal impairment (CLcr 30 to < 90 mL/min using the Cockcroft-Gault equation) compared to patients with normal renal function. The effect of severe renal impairment (CLcr 15 to < 30 mL/min) or end-stage renal disease with or without dialysis on pharmacokinetics of tisotumab vedotin-tftv and unconjugated MMAE is unknown.
Patients with Hepatic Impairment
Unconjugated MMAE exposures were 37% higher, but there were no clinically significant differences in exposures of tisotumab vedotin-tftv in patients with mild hepatic impairment compared to patients with normal hepatic function. The effect of moderate or severe hepatic impairment or liver transplantation on the pharmacokinetics of tisotumab vedotin-tftv or unconjugated MMAE is unknown.
Drug Interaction Studies
Clinical Studies
No clinical studies evaluating the drug-drug interaction potential of tisotumab vedotin-tftv have been conducted. To characterize the drug-drug interaction potential of unconjugated MMAE, clinical studies with another ADC that contains MMAE are described below, and similar effects on tisotumab vedotin-tftv and unconjugated MMAE exposures are expected with concomitant use of TIVDAK.
There were no clinically significant differences in midazolam (sensitive CYP3A4 substrate) pharmacokinetics when used concomitantly with another ADC that contains MMAE.
Strong CYP3A4 Inhibitors: Ketoconazole (strong CYP3A4 inhibitor) used concomitantly with another ADC that contains MMAE increased unconjugated MMAE Cmax by 25% and AUC by 34%, with no change in ADC exposure.
Strong CYP3A4 Inducers: Rifampin (strong CYP3A4 inducer) used concomitantly with another ADC that contains MMAE decreased unconjugated MMAE Cmax by 44% and AUC by 46%, with no change in ADC exposure.
In Vitro Studies
Cytochrome P450 (CYP) Enzymes: MMAE does not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP2D6. MMAE did not induce any major CYP450 enzymes in human hepatocytes.
Transporter Systems: MMAE is a substrate of P-glycoprotein (P-gp), but not an inhibitor of P-gp.
The observed incidence of anti-drug antibodies (ADA) is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of ADA in the studies described below with the incidence of ADA in other studies, including those of TIVDAK or of other tisotumab vedotin products.
In patients with recurrent or metastatic cervical cancer who were treated with TIVDAK 2 mg/kg every 3 weeks for up to 19 months (innovaTV 301) and 40 months (innovaTV 204), the incidence of anti-tisotumab vedotin-tftv antibody formation was 5.7% (12/211) and 5.4% (5/93), respectively. The incidence of neutralizing anti-tisotumab vedotin-tftv antibody formation was 0% (0/211) in innovaTV 301 using cell-based assay, and the incidence was 2.2% (2/93) in innovaTV 204 using Enzyme-linked Immunosorbent Assay (ELISA)-based assay. Given the low number of patients who developed anti-tisotumab vedotin-tftv antibodies, no conclusions can be drawn concerning a potential effect of immunogenicity on pharmacokinetics, efficacy or safety.
Tisotumab vedotin-tftv is a tissue factor (TF)-directed antibody drug conjugate (ADC). The antibody is a human IgG1 directed against cell surface TF. TF is the primary initiator of the extrinsic blood coagulation cascade. The small molecule, MMAE, is a microtubule-disrupting agent, attached to the antibody via a protease-cleavable linker. Nonclinical data suggests that the anticancer activity of tisotumab vedotin-tftv is due to the binding of the ADC to TF expressing cancer cells, followed by internalization of the ADC-TF complex, and release of MMAE via proteolytic cleavage. MMAE disrupts the microtubule network of actively dividing cells, leading to cell cycle arrest and apoptotic cell death. In vitro, tisotumab vedotin-tftv also mediates antibody-dependent cellular phagocytosis and antibody-dependent cellular cytotoxicity.
Tisotumab vedotin-tftv exposure-response relationships and the time course of pharmacodynamics response have not been fully characterized.
Cardiac Electrophysiology
At the recommended dose, tisotumab vedotin-tftv had no large mean effect on QTc prolongation (>20 msec).
Table 8 summarizes the exposure parameters of tisotumab vedotin-tftv and unconjugated MMAE (the cytotoxic component of tisotumab vedotin-tftv) following administration of one 3-week cycle of tisotumab vedotin-tftv 2 mg/kg to patients. Tisotumab vedotin-tftv concentrations peaked near the end of the infusion, while unconjugated MMAE concentrations peaked approximately 2 to 3 days after tisotumab vedotin-tftv dosing. Tisotumab vedotin-tftv Cmax increased proportionally, while AUC0-last increased in a more than dose-proportional manner, after a single dose ranging from 0.3–2.2 mg/kg (0.15 to 1.1 times the approved recommended dose). There was no accumulation of tisotumab vedotin-tftv and unconjugated MMAE. Steady-state concentrations of tisotumab vedotin-tftv and unconjugated MMAE were reached after 1 treatment cycle.
| Cmax=maximum concentration, AUC = area under the concentration-time curve from time 0 to 21 days (3 weeks) | ||
| Tisotumab Vedotin-tftv | Unconjugated MMAE |
Cmax | 40.8 (8.12) μg/mL | 5.91 (4.2) ng/mL |
AUC | 57.5 (13.4) day*μg/mL | 50 (35.8) day*ng/mL |
Distribution
The tisotumab vedotin-tftv steady state volume of distribution is 7.83 (%CV: 19.1) L. Plasma protein binding of MMAE ranged from 68% to 82%, in vitro.
Elimination
The median terminal half-life of tisotumab vedotin-tftv and unconjugated MMAE is 4.04 (range: 2.26-7.25) days and 2.56 (range: 1.81-4.10) days, respectively. The linear clearance of tisotumab vedotin-tftv and unconjugated MMAE was 1.54 (%CV: 28.8) L/day and 45.9 (%CV: 61.1) L/day, respectively. Elimination of MMAE appeared to be limited by its rate of release from tisotumab vedotin-tftv.
Metabolism
Tisotumab vedotin-tftv is expected to undergo catabolism to small peptides, amino acids, unconjugated MMAE, and unconjugated MMAE-related catabolites. Tisotumab vedotin-tftv releases unconjugated MMAE via proteolytic cleavage, and unconjugated MMAE is primarily metabolized by CYP3A4 in vitro.
Excretion
The excretion of tisotumab vedotin-tftv is not fully characterized. Following a single-dose of another ADC that contains MMAE, 17% of the total MMAE administered was recovered in feces and 6% in urine over a 1-week period, primarily as unchanged drug. A similar excretion profile of MMAE is expected after tisotumab vedotin-tftv administration.
Specific Populations
No clinically significant differences in the pharmacokinetics of tisotumab vedotin-tftv were observed based on age (21 to 81 years), sex, race (white vs non-white) or ethnicity (Hispanic or Latino vs non-Hispanic or non-Latino). No clinically significant differences in exposures of tisotumab vedotin-tftv and unconjugated MMAE were observed in patients with mild to moderate renal impairment (CLcr 30 to < 90 mL/min using the Cockcroft-Gault equation) compared to patients with normal renal function. The effect of severe renal impairment (CLcr 15 to < 30 mL/min) or end-stage renal disease with or without dialysis on pharmacokinetics of tisotumab vedotin-tftv and unconjugated MMAE is unknown.
Patients with Hepatic Impairment
Unconjugated MMAE exposures were 37% higher, but there were no clinically significant differences in exposures of tisotumab vedotin-tftv in patients with mild hepatic impairment compared to patients with normal hepatic function. The effect of moderate or severe hepatic impairment or liver transplantation on the pharmacokinetics of tisotumab vedotin-tftv or unconjugated MMAE is unknown.
Drug Interaction Studies
Clinical Studies
No clinical studies evaluating the drug-drug interaction potential of tisotumab vedotin-tftv have been conducted. To characterize the drug-drug interaction potential of unconjugated MMAE, clinical studies with another ADC that contains MMAE are described below, and similar effects on tisotumab vedotin-tftv and unconjugated MMAE exposures are expected with concomitant use of TIVDAK.
There were no clinically significant differences in midazolam (sensitive CYP3A4 substrate) pharmacokinetics when used concomitantly with another ADC that contains MMAE.
Strong CYP3A4 Inhibitors: Ketoconazole (strong CYP3A4 inhibitor) used concomitantly with another ADC that contains MMAE increased unconjugated MMAE Cmax by 25% and AUC by 34%, with no change in ADC exposure.
Strong CYP3A4 Inducers: Rifampin (strong CYP3A4 inducer) used concomitantly with another ADC that contains MMAE decreased unconjugated MMAE Cmax by 44% and AUC by 46%, with no change in ADC exposure.
In Vitro Studies
Cytochrome P450 (CYP) Enzymes: MMAE does not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP2D6. MMAE did not induce any major CYP450 enzymes in human hepatocytes.
Transporter Systems: MMAE is a substrate of P-glycoprotein (P-gp), but not an inhibitor of P-gp.
The observed incidence of anti-drug antibodies (ADA) is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of ADA in the studies described below with the incidence of ADA in other studies, including those of TIVDAK or of other tisotumab vedotin products.
In patients with recurrent or metastatic cervical cancer who were treated with TIVDAK 2 mg/kg every 3 weeks for up to 19 months (innovaTV 301) and 40 months (innovaTV 204), the incidence of anti-tisotumab vedotin-tftv antibody formation was 5.7% (12/211) and 5.4% (5/93), respectively. The incidence of neutralizing anti-tisotumab vedotin-tftv antibody formation was 0% (0/211) in innovaTV 301 using cell-based assay, and the incidence was 2.2% (2/93) in innovaTV 204 using Enzyme-linked Immunosorbent Assay (ELISA)-based assay. Given the low number of patients who developed anti-tisotumab vedotin-tftv antibodies, no conclusions can be drawn concerning a potential effect of immunogenicity on pharmacokinetics, efficacy or safety.
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