[p1–042]: plasma pharmacokinetics and pharmacodynamics of solanezumab in mild and moderate ad patients

Solanezumab is a monoclonal antibody binding to a mid-domain epitope on soluble Aβ species. Solanezumab has been studied in three double-blind Phase 3 clinical trials (EXPEDITION, NCT00905372; EXPEDITION2, NCT00904683; EXPEDITION3, NCT01900665). EXPEDITION and EXPEDITION2 were conducted in patients with mild- to moderate-AD, without regard to the presence of amyloid pathology. EXPEDITION3 was conducted in mild AD patients with evidence of amyloid pathology. An assessment of the pharmacokinetics (PK) and pharmacodynamics (PD) of solanezumab was incorporated into these trials to determine the extent that patient-specific factors influenced exposure and drug response. Data from EXPEDITION and EXPEDITION2 were combined to develop a population PK model. A two compartment structural model was fit to the data using NONMEM (Version 7.2). Various statistical models were explored to describe inter-patient and residual variability. Clinical and demographic parameters were retained in the model if statistically significant (p<0.01). A mechanistic PK/PD model was developed using equilibrium binding theory to describe the relationship between plasma solanezumab and Aβ1–40 concentrations. Data from EXPEDITION3 were used to evaluate the PK/PD model. Typical population values of clearance (CL) and intercompartmental clearance were estimated as 8.15 mL/hr and 10.3 mL/hr, respectively. The typical population values of central (V1) and peripheral volumes of distribution were determined to be 2780 mL and 2470 mL, respectively. Inter-patient variability in CL and V1 were 23.3% and 46.4%, respectively. The final model suggested that Asian race, body weight, and gender had a statistically significant influence on the PK of solanezumab, although these effects were not large and not thought to be clinically meaningful. The PK/PD model estimated the apparent binding coefficient between solanezumab and Aβ1–40 to be 6.51 ng/mL, suggesting a free plasma Aβ reduction at steady state of ∼91%. The evaluation of PK/PD models using EXPEDITION3 data will be presented. A PK model developed with data from mild and moderate AD patients found no clinically meaningful patient-specific factors influencing solanezumab exposure. This work suggests that exposures and drug effect are generally similar between patients across gender, disease severity, age, body weight, and racial groups.