Population pharmacokinetics of Elranatamab in patients with relapsed/refractory multiple myeloma from the Phase 1 ?rst-in-patient study (MagnetisMM-1)
Objectives: Elranatamab (PF-06863135) is a humanized heterodimeric bispecific molecule that targets B-cell maturation antigen (BCMA) on multiple myeloma cells and CD3 on T cells. To support the early development of elranatamab, a population pharmacokinetic (PK) model was developed using preliminary PK data from patients with relapsed/refractory multiple myeloma (RRMM) who received elranatamab as monotherapy during dose escalation in the Phase 1 ?rst-in-patient study (MagnetisMM-1, Study C1071001) using dosing adjusted for body weight. Potential covariates that may be important predictors of variability in total elranatamab exposures were evaluated to guide further development including the use of a fixed dosing approach.
Methods: The population PK analysis was performed using nonlinear mixed-effects modeling methodology as implemented in NONMEM (ICON Development Solutions, Ellicott City, MD). Potential covariates were assessed using the stepwise covariate model building procedure (SCM) in Perl-speaks-NONMEM (PsN). At the time of this analysis, PK data for total elranatamab were available from dose escalation in MagnetisMM-1, including 23 participants who received elranatamab 0.1-50 µg/kg IV weekly (QW) and 30 participants who received elranatamab 80-1000 µg/kg SC QW.
Results: Based on 854 total PK observations from 53 participants, the PK of total elranatamab was described using a 2-compartment model with first-order absorption and linear clearance. None of the following potential covariates were found to be clinically relevant predictors of total elranatamab exposures: baseline body weight, age, sex, race, baseline creatinine clearance (CRCL), baseline soluble BCMA (sBCMA), and immunogenicity (negative or positive ADA status). The estimated clearance (CL) was 0.296 L/d, the estimated central volume of distribution (Vc) and peripheral volume of distribution (Vp) were 4.74 L and 6.01 L, respectively, for a steady-state volume of distribution of approximately 11 L. The estimated inter-compartmental clearance (Q) was 0.143 L/day. The estimated first-order absorption rate constant (ka) was 0.212 day-1 and the estimated bioavailability (F) was 62.8%.
Conclusions: Based on this preliminary population PK analysis, no significant covariate relationships were retained in the final model. Body weight did not have a clinically relevant t impact on the PK of elranatamab, and this important result supports a fixed dosing approach.
Author(s)
- Jennifer E. Hibma, Pfizer, Inc. (Presenting Author)
- Sibo Jiang, Pfizer, Inc. (CoAuthor)
- Hoi-Kei Lon, Pfizer, Inc. (CoAuthor)
- Edward M. Chan, Pfizer, Inc. (CoAuthor)
- Athanasia Skoura, Pfizer, Inc. (CoAuthor)
- Diane Wang, Pfizer, Inc. (CoAuthor)
- Mohamed Elmeliegy, Pfizer, Inc. (CoAuthor)
- Donghua Yin, Pfizer, Inc. (CoAuthor)