ELAHERE Solution for injection Ref.[107263] Active ingredients: Mirvetuximab soravtansine

Exposure-Response Relationships

An exposure-response relationship between mirvetuximab soravtansine-gynx and overall response rates was observed. Higher incidence of Grade ≥2 ocular adverse reactions and Grade ≥2 peripheral neuropathy occurred with increasing mirvetuximab soravtansine-gynx exposure.

Cardiac Electrophysiology

At the approved recommended dose, ELAHERE did not cause large mean increases (>10 msec) in the QTc interval.

The pharmacokinetics were characterized after patients were administered mirvetuximab soravtansine-gynx 0.161 mg/kg to 8.71 mg/kg adjusted ideal body weight (AIBW) dosages, (0.0268 times to 1.45 times the approved recommended dosage of 6 mg/kg AIBW), unless otherwise noted.

Table 6 summarizes the exposure parameters of mirvetuximab soravtansine-gynx, unconjugated DM4, and its metabolite S-methyl-DM4 following administration after the first cycle (3-weeks) of mirvetuximab soravtansine-gynx 6 mg/kg to patients. Peak mirvetuximab soravtansine-gynx concentrations were observed near the end of intravenous infusion, while peak unconjugated DM4 concentrations were observed on the second day after administration of mirvetuximab soravtansine-gynx, and the peak S-methyl-DM4 concentrations were observed approximately 3 days after administration of mirvetuximab soravtansine-gynx. Steady state concentrations of mirvetuximab soravtansine-gynx, DM4, and S-methyl-DM4 were reached after 1 treatment cycle. Accumulation of the mirvetuximab soravtansine-gynx, DM4, and S-methyl-DM4 was minimal following repeat administration of mirvetuximab soravtansine-gynx.

Table 6. Exposure Parameters of Mirvetuximab Soravtansine-gynx, Unconjugated DM4, and S-methyl DM4 After First Treatment Cycle of 6 mg/kg of Mirvetuximab Soravtansine-gynx:

C_max = maximum concentration, AUC_tau = area under the concentration vs. time curve over the dosing interval (21 days).

Distribution

The mean (±SD) steady state volume of distribution of mirvetuximab soravtansine-gynx was 2.63 (±2.98) L.

Human plasma protein binding of DM4 and S-methyl DM4 was >99%, in vitro.

Elimination

Total plasma clearance (geometric mean [CV%]) of mirvetuximab soravtansine-gynx was 18.9 mL/hour (51.9%). The geometric mean terminal phase half-life of mirvetuximab soravtansine-gynx after the first dose was 4.8 days leading to a steady state at approximately 24 days. For the unconjugated DM4, the total plasma clearance (geometric mean [CV%]) was 13.8 L/hour (31.1%) and the geometric mean terminal phase half-life was 2.8 days. For S-methyl-DM4, the total plasma clearance (geometric mean [CV%]) was 4.3 L/hour (63.6%) and the geometric mean terminal phase half-life was 5.0 days.

Metabolism

The monoclonal antibody portion of mirvetuximab soravtansine-gynx is expected to be metabolized into small peptides by catabolic pathways. Unconjugated DM4 and S-methyl-DM4 undergo metabolism by CYP3A4. In human plasma, DM4 and S-methyl DM4 were identified as the main circulating metabolites, accounting for approximately 0.4% and 1.4% of mirvetuximab soravtansine-gynx AUCs, respectively.

Excretion

S-methyl DM4 and DM4-sulfo-SPDB-lysine were detected in urine within 24 hours of infusion as the main metabolites.

Specific Populations

No clinically significant differences in the pharmacokinetics of mirvetuximab soravtansine-gynx were observed based on age (34 to 89 years), body weight (36 to 136 kg), mild hepatic impairment (total bilirubin ≤ULN and any AST >ULN or total bilirubin >1 to 1.5 times ULN and any AST), or mild to moderate renal impairment (CLcr ≥30 and <90 mL/min).

The pharmacokinetics of ELAHERE in patients with moderate to severe hepatic impairment (total bilirubin >1.5 ULN with any AST) or severe renal impairment (CLcr 15 to 30 mL/min) is unknown.

Drug Interaction Studies

Clinical studies and model informed approaches

No clinical studies evaluating the drug-drug interaction potential of mirvetuximab soravtansine-gynx have been conducted.

However, in 3 clinical trials, there were no differences in exposure between patients who received concomitant weak or moderate CYP3A4 inhibitors or P-glycoprotein (P-gp) inhibitors and those who did not.

In Vitro Studies

Cytochrome P450 (CYP) Enzymes: Unconjugated DM4 is a time-dependent inhibitor of CYP3A4. Unconjugated DM4 and S-methyl DM4 are not direct inhibitors of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or CYP3A. DM4 and S-methyl DM4 are not inducers of CYP1A2, CYP2B6, or CYP3A4.

Transporter Systems: Unconjugated DM4 and S-methyl DM4 are substrates of P-gp but are not inhibitors of P-gp.

Carcinogenicity studies have not been conducted with mirvetuximab soravtansine-gynx or DM4.

DM4 and the metabolite, S-methyl DM4, were clastogenic in the in vivo rat bone marrow micronucleus study. DM4 and S-methyl DM4 were not mutagenic in the bacterial reverse mutation (Ames) assay.

Fertility studies have not been conducted with mirvetuximab soravtansine-gynx or DM4.