Clinical pharmacology of the antibody–drug conjugate enfortumab vedotin in advanced urothelial carcinoma and other malignant solid tumors Review
| Authors: | Tang, M.; Garg, A.; Bonate, P. L.; Rosenberg, J. E.; Matsangou, M.; Kadokura, T.; Yamada, A.; Choules, M.; Pavese, J.; Nagata, M.; Tenmizu, D.; Koibuchi, A.; Heo, N.; Wang, L.; Wojtkowski, T.; Hanley, W. D.; Poondru, S. |
| Review Title: | Clinical pharmacology of the antibody–drug conjugate enfortumab vedotin in advanced urothelial carcinoma and other malignant solid tumors |
| Abstract: | Enfortumab vedotin is an antibody–drug conjugate comprised of a human monoclonal antibody directed to Nectin-4 and monomethyl auristatin E (MMAE), a microtubule-disrupting agent. The objectives of this review are to summarize the clinical pharmacology of enfortumab vedotin monotherapy and demonstrate that the appropriate dose has been selected for clinical use. Pharmacokinetics (PK) of enfortumab vedotin (antibody–drug conjugate and total antibody) and free MMAE were evaluated in five clinical trials of patients with locally advanced or metastatic urothelial carcinoma (n = 748). Intravenous enfortumab vedotin 0.5–1.25 mg/kg on days 1, 8, and 15 of a 28-day cycle showed linear, dose-proportional PK. No significant differences in exposure or safety of enfortumab vedotin and free MMAE were observed in mild, moderate, or severe renal impairment versus normal renal function. Patients with mildly impaired versus normal hepatic function had a 37% increase in area under the concentration-time curve (0–28 days), a 31% increase in maximum concentration of free MMAE, and a similar adverse event profile. No clinically significant PK differences were observed based on race/ethnicity with weight-based dosing, and no clinically meaningful QT prolongation was observed. Concomitant use with dual P-glycoprotein and strong cytochrome P450 3A4 inhibitors may increase MMAE exposure and the risk of adverse events. Approximately 3% of patients developed antitherapeutic antibodies against enfortumab vedotin 1.25 mg/kg. These findings support enfortumab vedotin 1.25 mg/kg monotherapy on days 1, 8, and 15 of a 28-day cycle. No dose adjustments are required for patients with renal impairment or mild hepatic impairment, or by race/ethnicity. © The Author(s) 2024. |
| Keywords: | review; advanced cancer; area under the curve; dose response; drug efficacy; drug safety; liver function; monotherapy; side effect; antineoplastic agents; skin manifestation; antineoplastic agent; cancer immunotherapy; metastasis; multiple cycle treatment; peripheral neuropathy; qt prolongation; body weight; pathology; dose-response relationship, drug; monoclonal antibody; hyperglycemia; rash; urologic neoplasms; antibodies, monoclonal; drug distribution; kidney function; drug response; drug metabolism; ketoconazole; carcinoma, transitional cell; azithromycin; rifampicin; oligopeptides; transitional cell carcinoma; atorvastatin; dose calculation; ethnicity; drug exposure; plasma concentration-time curve; erythromycin; drug elimination; phase 2 clinical trial (topic); phase 3 clinical trial (topic); cytochrome p450 3a4; phase 1 clinical trial (topic); antibody conjugate; immunoconjugates; oligopeptide; demographics; clinical pharmacology; urinary tract tumor; quinidine; nectins; synergistic effect; humans; human; vedotin; severe renal impairment; monoclonal antibody therapy; solid malignant neoplasm; mild renal impairment; maximum concentration; abc transporter subfamily b; enfortumab vedotin; nectin; mild hepatic impairment; moderate renal impairment; nectin4 protein, human |
| Journal Title: | Clinical Pharmacokinetics |
| Volume: | 63 |
| Issue: | 4 |
| ISSN: | 0312-5963 |
| Publisher: | Adis International Ltd |
| Date Published: | 2024-04-01 |
| Start Page: | 423 |
| End Page: | 438 |
| Language: | English |
| DOI: | 10.1007/s40262-024-01369-0 |
| PUBMED: | 38609704 |
| PROVIDER: | scopus |
| PMCID: | PMC11052883 |
| DOI/URL: | |
| Notes: | The MSK Cancer Center Support Grant (P30 CA008748) is acknowledged in the PDF -- Source: Scopus |
