Physiologically based pharmacokinetic model to predict drug –drug interactions with the antibody–drug conjugate enfortumab vedotin

AbstractEnfortumab vedotin is an antibody –drug conjugate (ADC) comprised of a Nectin-4–directed antibody and monomethyl auristatin E (MMAE), which is primarily eliminated through P-glycoprotein (P-gp)–mediated excretion and cytochrome P450 3A4 (CYP3A4)–mediated metabolism. A physiologically based pharmacokinetic (PBPK) model was de veloped to predict effects of combined P-gp with CYP3A4 inhibitor/inducer (ketoconazole/rifampin) on MMAE exposure when coadministered with enfortumab vedotin and study enfortumab vedotin with CYP3A4 (midazolam) and P-gp (digoxin) substrate exposure. A PBPK model was built for enfortumab vedotin and unconjugated MMAE using the PBPK simulator ADC module. A similar model was developed with brentuximab vedotin, an ADC with the same valine-citrulline–MMAE linker as enfortumab vedotin, for MMAE drug–drug interaction (DDI) verification using clinical data. The DDI simulation predicted a less-tha n-2-fold increase in MMAE exposure with enfortumab vedotin plus ketoconazole (MMAE geometric mean ratio [GMR] for maximum concentration [Cmax], 1.15; GMR for area under the time-concentration curve from time 0 to last quantifiable concentration [AUClast], 1.38). Decreased MMAE exposure above 50% but below 80% was observed with enfortumab vedotin plus rifampin (MMAE GMR Cmax, 0.72; GMR AUClast, 0.47). No effect of enfortumab vedotin on midazolam or digoxin systemic exposure was predicted. Results suggest that combination enfortumab vedotin, P-gp, and ...
Source: Journal of Pharmacokinetics and Pharmacodynamics - Category: Drugs & Pharmacology Source Type: research