Population Pharmacokinetic Analysis of Elranatamab in Patients with Multiple Myeloma
Jennifer E. Hibma (1), Mohamed Elmeliegy (1) Lindsay E King (1), Frederick McCush (1), Diane Wang (1), Jason H. Williams (1)
Pfizer Inc., La Jolla, CA (1)
Introduction: PF-06863135 (Elranatamab) is a T-cell redirecting bispecific antibody targeting both B-cell Maturation Antigen (BCMA) and the T-cell co-receptor CD3. Elranatamab is being investigated for the treatment of multiple myeloma. To fully characterize the population pharmacokinetics (PK) of elranatamab and to evaluate potential covariates that may be important predictors of variability in elranatamab PK, this population PK analysis was conducted using available data from Studies C1071001, C1071002, C1071003, and C1071009.
Objectives:
- To characterize the population PK of free and total elranatamab
- To identify potential covariates that may be important predictors of variability in free and total elranatamab PK
Methods: Target-mediated drug disposition (TMDD) models and various approximations that have been used to describe the PK of bispecific drugs [1] and other protein drugs with disposition influenced by receptor interaction [2] were evaluated to incorporate the binding of elranatamab to sBCMA. The model was parameterized in terms of the three entities; free elranatamab, free sBCMA, and the elranatamab-sBCMA complex, each with their own clearance and volume of distribution [3]. Validated electrochemiluminescent (ECL) ligand binding assays were used to determine free and total elranatamab and free sBCMA concentration and an immunoaffinity LC-MS/MS assay was validated for the quantification of total sBCMA. The elranatamab and sBCMA concentrations and dose amounts were converted from ng/mL to molar units (nM) using the molecular weights of elranatamab (148 kilodalton (kDa)) and sBCMA (5.4 kDa). The relationship between these entities assumes that they are always at equilibrium.
Results: In total there were 13233 observations from 321 participants who received IV or SC elranatamab monotherapy from first-in-patient and Phase 2 Studies C1071001, C1071002, C1071003, and C1071009. The typical value for elranatamab clearance (CL) was 0.324 L/d (100% CV), sBCMA clearance was 0.273 L/d (448% CV), and the clearance of the elranatamab:sBCMA complex was 0.164 L/d (79%CV). The volume of distribution for elranatamab (Vc) was 4.78 L for the central compartment and was 2.83 L for the peripheral compartment. Similarly, the volume of distribution for the complex (elranatamab:sBCMA) was 3.80 L. The volume of distribution for sBCMA was somewhat larger, 15.4 L, which is expected given its smaller size (5.4 kDA for sBCMA versus 148 kDA for elranatamab). Bioavailability of elranatamab following SC administration was estimated to be 56.2% and the typical value of absorption rate constant (ka) was 0.287 1/day (68% CV). The accumulation ratio for AUC and Cmax were approximately 4.8 and 8.0 for total elranatamab, respectively, and were 6.6 and 11.2 for free elranatamab, respectively. The time to 50% elranatamab exposure reduction was approximately 25 days. All model parameters were estimated with good precision (relative standard error (RSE) < 30%), were within the 95% CIs, and are in agreement with published values for monoclonal antibodies (mABs).[4]
In the stepwise covariate model building analysis, three variables were statistically significant yet their clinical impact on elranatamab exposure was considered not clinically relevant: age on first-order absorption rate constant (ka), sex on clearance (CL), and body weight on central volume of distribution (Vc). Thus, fixed-dosing of elranatamab is supported. No other significant relationships were identified for elranatamab CL, Vc and ka, including potential covariate sBCMA.
Conclusions:
- Total and free elranatamab PK was well described using a semi-mechanistic two-compartment target-binding model with linear clearance, and first order absorption.
- Based on the covariate analyses, including immunogenicity, estimated Glomerular Filtration rate (eGFR), albumin, sBCMA, age, sex, and body weight, none of the potential covariates were found to be clinically significant predictors of elranatamab exposure.
- The final population PK model for elranatamab that included data from 321 patients who received elranatamab monotherapy in studies C1071001, C1071002, C1071003, and C1071009, is adequate for predicting post-hoc total and free elranatamab exposure metrics that can be used for subsequent E-R analyses with efficacy and safety endpoints.
References:
[1] Schropp J, Khot A, Shah D and Koch G, 2019, Target- mediated drug disposition model
for bispecific antibodies: Properties, approximation, and optimal dosing strategy. CPT
Pharmacometrics Syst Pharmacol vol. 8: 177–187.
[2] Dua P, Hawkins E and van der Graaf P, 2015, A tutorial on target-mediated drug
disposition (tmdd) models. CPT Pharmacometrics Syst Pharmacol vol. 4: 324–337.
[3] Hayashi N, Tsukamoto Y, Sallas W and Lowe P, 2007, A mechanism-based binding
model for the population pharmacokinetics and pharmacodynamics of omalizumab. Br J
Clin Pharmacol vol. 63: 548–561.
[4] Dirks N and Meibohm B, 2010, Population pharmacokinetics of therapeutic
monocolonal antibodies. Clin Pharmacokinet vol. 49: 633–59.