Population Pharmacokinetic Modeling of Different Formulations of Inclacumab Using Phase 1 Data in Healthy Participants

Abstract

Introduction: P-selectin is a cell adhesion molecule that contributes to vaso-occlusive crises (VOCs) in sickle cell disease (SCD). Inclacumab is a recombinant, fully human, immunoglobulin G4 monoclonal antibody that selectively binds to P-selectin to prevent binding with P-selectin glycoprotein ligand-1. Inclacumab was previously evaluated by Roche in clinical trials with healthy participants and patients with cardiovascular disease and is now being developed as a potential treatment to reduce the frequency of VOCs in individuals with SCD. Changes in the manufacturing of inclacumab have resulted in 3 formulations/drug materials: Roche v0.1, Roche v0.2, and Global Blood Therapeutics (GBT). GBT-manufactured inclacumab utilizes a similar formulation and the same cell line as Roche v0.2 (Roche v0.1 utilizes a different cell line), and analytical and nonclinical comparability between Roche v0.2 and GBT inclacumab have been demonstrated (Mihaila et al. Expert Opin Biol Ther 2022). Here we report results from a population pharmacokinetic (PopPK) model developed to compare the pharmacokinetics (PK) of different formulations using data from 4 phase 1 clinical studies in healthy participants administered Roche v0.1, Roche v0.2, or GBT inclacumab. The objectives were to develop a PopPK model to describe inclacumab PK in healthy adult participants and to quantify potential differences in inclacumab PK associated with different formulations/drug materials. Methods: A PopPK model was developed using single- and multiple-dose PK data from healthy participants who received intravenous (IV) inclacumab across 4 studies (BP21112 [Roche v0.1, single ascending dose (SAD)], BP21617 [Roche v0.1, multiple ascending dose], BP28134 [Roche v0.2, SAD], and GBT2104-111 [GBT, SAD]). Evaluable participants had ≥1 measurable postdose concentration with an associated sample time, relevant dosing information prior to each measurable concentration, and no protocol violation that could confound PK analyses. A nonlinear mixed effects model was fit to the inclacumab plasma concentration-time data using first-order conditional estimation with eta-epsilon interaction in NONMEM ® (v7.3). Model selection was based on the plausibility of parameter estimates, goodness-of-fit plots, and the objective function value. The final model was evaluated using a prediction-corrected visual predictive check (pcVPC). Results: The PopPK dataset comprised 145 healthy participants, of which 2622 inclacumab plasma concentrations (84.9%) from 143 participants were evaluable (Roche v0.1: n=68 [47.6%]; Roche v0.2: n=60 [42.0%]; GBT: n=15 [10.5%]). Median (range) age and body weight were 42 (21-63) years and 73.2 (45.8-109) kg, respectively. Nominal doses ranged from 0.03 to 40 mg/kg IV; 23.8% of participants received 3 mg/kg and 29.4% received 20 mg/kg. A 3-compartment disposition model with parallel linear clearance (CL=0.125 L/d) and nonlinear (concentration-dependent; V max=1.19 mg/d; K m=0.784 μg/mL) clearance from the central compartment described the plasma concentration-time data. The effect of drug material was incorporated a priori as relative bioavailability term F in the base model using exploratory analyses of observed exposures. Dosing of Roche v0.1 and Roche v0.2 inclacumab resulted in 23% and 2% higher exposure than GBT inclacumab, respectively. Between-subject variability was estimated for linear clearance, nonlinear clearance, and all volume parameters, and residual error was described using a proportional model (Table). Of the tested covariates, baseline body weight was a statistically significant covariate effect and was included on all linear clearance and volume terms. Model qualification by pcVPC showed good predictive performance of the final model. Conclusions: The PopPK of IV inclacumab in healthy participants was described by a 3-compartment disposition model with parallel linear and nonlinear clearances. Estimated relative exposure of Roche v0.2 and GBT-manufactured inclacumab was similar, indicating comparability in drug exposure. Understanding the relationship between exposure and dose for different formulations facilitates more accurate assessment of safety data across multiple clinical studies. These data provide support for the ongoing phase 3 clinical development in SCD using GBT-manufactured inclacumab without further clinical comparability testing.