TIVDAK
Clinical safety rating: caution
Comprehensive clinical and safety monograph for TIVDAK (TIVDAK).
Tisotumab vedotin-tftv is an antibody-drug conjugate (ADC) composed of a monoclonal antibody targeting tissue factor (TF) conjugated to monomethyl auristatin E (MMAE), a microtubule-disrupting agent. The antibody binds to TF on tumor cells, leading to internalization and release of MMAE, which inhibits cell division and induces apoptosis.
| Metabolism | MMAE is primarily metabolized by CYP3A4. The ADC is expected to be catabolized to small peptides, amino acids, and unconjugated MMAE. |
| Excretion | Tivdak (tisotumab vedotin-tftv) is primarily eliminated via hepatic metabolism to small peptide and amino acid components, with the antibody backbone catabolized to amino acids. The MMAE payload is mostly eliminated in feces (86%) and urine (17%) as unchanged drug or metabolites, with <1% excreted renally as unchanged MMAE. |
| Half-life | Terminal elimination half-life of tisotumab vedotin-tftv is approximately 4.0 days (range 2.7-6.4 days) for the antibody-drug conjugate (ADC) and 2.5 days (range 1.1-3.5 days) for monomethyl auristatin E (MMAE). This half-life supports a 3-week dosing interval, achieving steady state by cycle 3. |
| Protein binding | MMAE is approximately 68-82% bound to human plasma proteins, primarily albumin and α-1-acid glycoprotein. Tisotumab vedotin-tftv antibody backbone binding not reported, but typical IgG binding is >99%. |
| Volume of Distribution | Volume of distribution at steady state (Vss) is 7-8 L for the ADC and 25-38 L for MMAE, indicating limited extravascular distribution for ADC and moderate distribution for free MMAE (approximately 0.15 L/kg for MMAE based on typical body weight). |
| Bioavailability | Not applicable (Tivdak is administered only as an intravenous infusion; no oral bioavailability). |
| Onset of Action | Intravenous administration: Clinical response (tumor shrinkage) typically observed after 2-3 cycles (6-9 weeks) based on clinical trials; maximal response may take longer. |
| Duration of Action | Duration of response ranges from 1.2 to 9.1 months (median 5.7 months) in responders; treatment continues until disease progression or unacceptable toxicity. |
2 mg/kg (up to 200 mg) intravenously over 30 minutes on day 1 of a 21-day cycle until disease progression or unacceptable toxicity.
| Dosage form | INJECTABLE |
| Renal impairment | No dose adjustment recommended for mild to moderate renal impairment (CLcr 30-89 mL/min). Not studied in severe renal impairment (CLcr <30 mL/min) or end-stage renal disease. |
| Liver impairment | Child-Pugh A: No dose adjustment. Child-Pugh B: Administer at 1.5 mg/kg (up to 150 mg). Child-Pugh C: Not recommended. |
| Pediatric use | Safety and efficacy in pediatric patients have not been established. |
| Geriatric use | No specific dose adjustment recommended. In clinical trials, no overall differences in safety or efficacy were observed between patients ≥65 years and younger patients, but limited data in those ≥75 years. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for TIVDAK (TIVDAK).
| Breastfeeding | No data are available on the presence of tisotumab vedotin in human milk, its effects on the breastfed infant, or milk production. Because of the potential for serious adverse reactions in breastfed infants, advise women not to breastfeed during treatment and for 2 months after the last dose. The M/P ratio is unknown. |
| Teratogenic Risk | Tisotumab vedotin is a cytotoxic ADC that disrupts microtubule function. Based on its mechanism and animal studies, it is expected to cause fetal harm when administered to pregnant women. There are no adequate human data. In animal reproduction studies, tisotumab vedotin was embryotoxic and teratogenic at exposures below the clinical dose. Advise of potential risks to a fetus. Use effective contraception during treatment and for 2 months after the last dose. |
■ FDA Black Box Warning
None.
| Serious Effects |
["None known."]
| Precautions | ["Ocular toxicity: Includes conjunctivitis, keratitis, dry eye, and corneal ulcers; requires ophthalmologic monitoring and management.","Peripheral neuropathy: Monitor for new or worsening neuropathy.","Hemorrhage: Severe bleeding events, including fatal cases, have occurred.","Pneumonitis: Fatal and life-threatening cases reported.","Embryo-fetal toxicity: Can cause fetal harm."] |
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| Fetal Monitoring | If TIVDAK is used during pregnancy, monitor for fetal growth and development with serial ultrasound. Assess amniotic fluid volume as oligohydramnios has been reported with other ADCs. Monitor for maternal toxicities including peripheral neuropathy, ocular toxicity, and bleeding, which may affect pregnancy management. |
| Fertility Effects | Based on animal studies, tisotumab vedotin may impair fertility in females. Ovarian toxicity, including depletion of primordial follicles, was observed in animal studies at exposures similar to clinical doses. The relevance to human fertility is unknown. Male fertility effects have not been studied but may occur due to microtubule disruption. |