Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

12.2 Pharmacodynamics
Exposure-Response Relationships
Higher exposure to mirvetuximab soravtansine was associated with higher overall response rates and longer median PFS and OS; higher exposure to mirvetuximab soravtansine was also associated with higher incidence of ocular adverse reactions as well as marginally increased peripheral neuropathy.
Cardiac Electrophysiology
At the approved recommended dose, ELAHERE did not cause large mean increases (>10 msec) in the QTc interval.

Pharmacokinetic Properties

12.3 Pharmacokinetics
The pharmacokinetics were characterized in patients who received mirvetuximab soravtansine 0.16 mg/kg to 8.7 mg/kg adjusted ideal body weight (AIBW) (0.03 times to 1.4 times the approved recommended dose of 6 mg/kg AIBW), unless otherwise noted.
Table 8 summarizes the exposure parameters of mirvetuximab soravtansine, unconjugated DM4, and its metabolite S-methyl-DM4 following administration after the first cycle (3-weeks). Peak mirvetuximab soravtansine concentrations were observed near the end of intravenous infusion, while peak unconjugated DM4 concentrations were observed on the second day after administration and the peak S-methyl-DM4 concentrations were observed approximately 3 days after administration. Steady state concentrations of mirvetuximab soravtansine, DM4, and S-methyl-DM4 were reached after one 3-week cycle. Accumulation of the mirvetuximab soravtansine, DM4, and S-methyl-DM4 was minimal following multiple cycles.
Table 8: Exposure Parameters of Mirvetuximab Soravtansine, Unconjugated DM4, and S-methyl DM4 After First Cycle at a Dosage of 6 mg/kg
Mirvetuximab Soravtansine                       Unconjugated DM4                 S-methyl-DM4 Mean (±SD)                                      Mean (±SD)                       Mean (±SD) Cmax              137.3 (±62.3) µg/mL                             4.1 (±2.3) ng/mL                 7.0 (±6.8) ng/mL AUCtau            20.6 (±6.8) h*mg/mL                             530 (±245) h*ng/mL               1848 (±1585) h*ng/mL Cmax = maximum concentration, AUCtau = 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 was 2.6 (±2.9) L.
Human plasma protein binding of DM4 and S-methyl DM4 was >99%, in vitro.
Elimination
For mirvetuximab soravtansine, total plasma clearance (mean [CV%]) of was 19 mL/hour (52%) and the mean terminal phase half-life 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 (mean [CV%]) was 14 L/hour (31%) and the mean terminal phase half-life was 2.8 days.
For S-methyl-DM4, the total plasma clearance (mean [CV%]) was 4.3 L/hour (64%) and the mean terminal phase half-life was 5 days.
Metabolism
The monoclonal antibody portion of mirvetuximab soravtansine 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 AUC, 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 soravtansinesoravtansine were observed based on age (32 to 89 years), race (White, Black, or Asian), 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 to 89 mL/min).
The pharmacokinetics of mirvetuximab soravtansine 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 to evaluate the drug-drug interaction potential of mirvetuximab soravtansine were conducted.
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 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.

12.6 Immunogenicity
The observed incidence of anti-drug antibodies (ADA), including neutralizing antibody, is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of ADAs in the studies described below with the incidence of ADAs to mirvetuximab soravtansine in other studies.
With a median treatment duration of 4.4 months in Studies 0416, 0417, 0401, and 0403, in patients with epithelial ovarian, fallopian tube, or primary peritoneal cancer who received mirvetuximab soravtansine at 6 mg/kg AIBW intravenously every 3 weeks, 9% (57/626) of patients developed anti-mirvetuximab soravtansine antibodies. Neutralizing antibodies were detected in 47% (27/57) of patients who were ADA-positive.
No clinically meaningful difference was observed in the trough concentrations of mirvetuximab soravtansine between ADA-positive and ADA-negative patients. Anti-mirvetuximab soravtansine antibody formation was associated with a higher incidence of infusion-related reactions [see Adverse Reactions (6.1)]. The effect of anti-drug antibodies on effectiveness has not been fully characterized. Based on limited data, the presence of anti-mirvetuximab soravtansine antibodies may be associated with decreased efficacy in ADA-positive patients when compared to ADA-negative patients.