Population Pharmacokinetics of a Monoclonal Antibody Tanezumab in Chronic Pelvic Pain Conditions
Adriaan Cleton (1), Bojan Lalovic (2), Rujia Xie (1) & Rosalin Arends (2)
Pfizer Development Primary Care Business Unit (1) Pfizer, Sandwich, UK; (2) Groton, CT, USA
Objectives: Tanezumab is a fully human monoclonal antibody targeted to the human nerve growth factor receptor (NGF). A comprehensive population pharmacokinetic model of tanezumab was developed using nonlinear mixed-effects modeling of 303 patients (3239 observations) with Chronic Pelvic Pain Conditions (Institual Cystitus, Chronic Prostatitus and Endometriosis) and osteoarthritis population based on 5 clinical studies using IV administration. The influence of demographics and population (OA versus Chronic Pelvic Pain) on the pharmacokinetics of tanezumab was explored.
Methods: Nonlinear mixed effects modeling methodology was implemented in this analysis using NONMEM® (version 6). The first-order conditional estimation (FOCE) method with interaction was used to fit tanezumab plasma concentration data. Stepwise forward selection was used to identify relationships between population PK parameters and selected covariates including baseline body weight, age and gender. Standard goodness-of-fit diagnostics and posterior predictive checks were used to evaluate the adequacy of the PK model fit and predictions.
Results: The disposition of tanezumab was best described with a 2-compartment model with parallel linear and nonlinear (Michaelis-Menten) elimination pathways. The population pharmacokinetic parameter estimates for this dataset were for the linear clearance (CL), the maximum nonlinear clearance (Vmax/Km), the central volume of distribution (V1), the peripheral volume of distribution (V2), and the Michaelis-Menten constant (Km) 0.182 L/d, 0.33 L/d, 3.4 L, 2.86 L, and 15.3 ng/mL, respectively. Body weight was found to be the most influential covariate on tanezumab exposure, affecting CL, V1 and V2. The presence of anti-tanezumab antibodies in patients was low and not evaluated as a covariate.
Conclusions: The population PK model adequately characterized tanezumab PK in subjects in Chronic Pelvic Pain and Osteoarthritis. Consistent with the expected behaviour of the monoclonal antibodies, no notable difference in the PK between the different patient populations was observed.