Population Pharmacokinetics of Mirvetuximab Soravtansine in Patients
with Folate Receptor-α Positive Ovarian Cancer: the Antibody-Drug
Conjugate, Payload and Metabolite
Abstract
Aims: Mirvetuximab soravtansine is the first-in-class antibody-drug
conjugate approved in November 2022 for the treatment of folate
receptor-α positive ovarian cancer. The aim of this study was to develop
a population pharmacokinetic (PK) model to describe the
concentration-time profiles of mirvetuximab soravtansine, the payload
(DM4) and a metabolite (S-methyl-DM4). Methods: Mirvetuximab
soravtansine was administered intravenously from 0.15 to 7 mg/kg to 543
patients with predominantly platinum-resistant ovarian cancer in three
clinical studies, and the plasma drug concentrations were analyzed using
a nonlinear mixed-effects modelling approach to estimate the PK
parameters, inter-individual variabilities, and residual errors.
Stepwise covariate modelling was performed to identify covariates.
Results: We developed a semi-mechanistic population PK model that
included linear and nonlinear routes for the elimination of mirvetuximab
soravtansine and a target compartment for the formation and disposition
of the payload and metabolite in tumor cells. The model adequately
described the concentration-time profiles for the three analytes.
Patient body weight, serum albumin, and age were identified as the major
covariates. Exposures in patients with renal or hepatic impairment were
estimated. The effect of inhibition of cytochrome P450 (CYP) 3A4 on drug
exposures was also evaluated. Conclusions: There is no need for dose
adjustment due to covariate effects for mirvetuximab soravtansine
administered at the recommended dose of 6 mg/kg based on adjusted ideal
body weight. The model also showed that dose adjustment is not required
for patients with mild or moderate renal impairment, mild hepatic
impairment, or when concomitant weak and moderate CYP3A4 inhibitors are
used.