Telisotuzumab vedotin is a c-Met-directed antibody drug conjugate (ADC). The antibody is a humanized IgG1κ directed against c-Met, the cell surface receptor for hepatocyte growth factor. The small molecule, MMAE, is a microtubule-disrupting agent, attached to the antibody via a protease cleavable linker. Following binding to c-Met-expressing cells, telisotuzumab vedotin undergoes internalization and intracellular cleavage of MMAE. MMAE disrupts the microtubule network of actively dividing cells, subsequently inducing cell cycle arrest and apoptotic cell death. Telisotuzumab vedotin exhibited antitumor activity in xenograft models of NSCLC.
Exposure-response relationships for efficacy and time course of pharmacodynamic response have not been fully characterized.
Higher telisotuzumab vedotin exposure was associated with increased rates of Grade 3 peripheral neuropathy, and Grades 2 and 3 ocular surface disorders. Higher unconjugated MMAE exposure was associated with increased rates of Grade ≥3 adverse reactions and fatal adverse reactions.
There is insufficient information to characterize the effect of telisotuzumab vedotin on the QT interval.
The exposure parameters of telisotuzumab vedotin (ADC) and unconjugated MMAE (cytotoxic component of telisotuzumab vedotin) are summarized in the table below. The plasma exposure of the ADC and unconjugated MMAE increased proportionally over a dose range of 1.2 to 3.3 mg/kg (0.64 to 1.7 times the approved recommended dose). ADC time to maximum plasma concentrations (Tmax) occurs at the end of intravenous infusion while MMAE Tmax occurs approximately 5 days after telisotuzumab vedotin administration. Minimal accumulation of the ADC or MMAE occurs.
Exposure Parameters of Telisotuzumab Vedotin (ADC) and Unconjugated MMAE at Telisotuzumab vedotin 1.9 mg/kg Every 2 Weeks:
| ADC | Unconjugated MMAE | |
|---|---|---|
| Cmax | 29 (43) µg/mL | 2.2 (53) ng/mL |
| AUC0-tau | 2,130 (55) µg∙hr/mL | 405 (64) ng∙hr/mL |
Cmax = maximum concentration
AUC0-tau = area under the concentration-time curve from time zero to 14 days (2 weeks)
The estimated volume of distribution is 3.4 L (16.5%CV) for telisotuzumab vedotin.
MMAE plasma protein binding ranges from 68% to 82% in vitro.
The elimination half-life is approximately 3 days for the ADC and approximately 4 days for MMAE. The estimated clearance (CL) is 1.3 L/day (31.5%CV) for the ADC and 76 L/day (52.1%CV) for MMAE.
Telisotuzumab 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 catabolites. MMAE is metabolized primarily by CYP3A4.
No clinically significant differences in the pharmacokinetics of the ADC or unconjugated MMAE were observed based on age (30 to 87 years), sex, race (65% White, 32% Asian, and 3% Black), body weight (34 to 144 kg), mild or moderate renal impairment (CLcr 30 to 89 mL/min, estimated by Cockcroft-Gault), or mild hepatic impairment (total bilirubin ≤ULN and AST >ULN or total bilirubin >ULN and ≤1.5 x ULN and any AST).
The effect of severe renal impairment (CLcr <30 mL/min), end-stage renal disease with or without dialysis, or moderate to severe hepatic impairment (total bilirubin >1.5 × ULN and any AST) on the pharmacokinetics of telisotuzumab vedotin or unconjugated MMAE is unknown.
No clinical studies have evaluated the potential for drug-drug interactions.
MMAE AUC is predicted to increase by 1.4-fold following concomitant administration of telisotuzumab vedotin with ketoconazole (a strong CYP3A inhibitor).
MMAE AUC is predicted to decrease by 70% following concomitant administration of telisotuzumab vedotin with rifampicin (a strong CYP3A inducer).
No clinically significant difference in the pharmacokinetics of midazolam (a sensitive CYP3A substrate) is predicted when used concomitantly with telisotuzumab vedotin.
MMAE is a substrate and an inhibitor of CYP3A4/5.
MMAE is a substrate of P-glycoprotein (P-gp).
© All content on this website, including data entry, data processing, decision support tools, "RxReasoner" logo and graphics, is the intellectual property of RxReasoner and is protected by copyright laws. Unauthorized reproduction or distribution of any part of this content without explicit written permission from RxReasoner is strictly prohibited. Any third-party content used on this site is acknowledged and utilized under fair use principles.