Population PKPD analysis of weekly pain scores after intravenously administered tanezumab, based on pooled Phase 3 data in patients with osteoarthritis of the knee or hip
E. Niclas Jonsson (1,2), Rosalin Arends (3), Rujia Xie (3) and Scott Marshall (3)
(1) Exprimo NV (2) now Pharmetheus AB, (3) Pfizer
Objectives: To characterize the relationship between tanezumab concentrations and weekly pain scores (WPS) over time (measured daily on a 0-10 numerical rating scale) after IV administration in patients with OA of the knee or hip, including covariate relationships and probability of dropout.
Methods: Data were available from four Phase 3 studies (n=2449) for which a population PK model previously had been developed. Separate models for the response and dropout probability after placebo and active treatment were developed. The final PKPD model described the WPS response as the sum of the tanezumab and the placebo effects. The impact of covariates was characterized for all models and simulations, integrated with the PK model, were used to quantify their impact on the clinically relevant endpoint - the baseline and placebo corrected WPS response at week 16, both with and without BOCF imputation.
Results: A set of exponential functions was used to describe the onset of placebo response after the first and subsequent doses. The higher placebo effect with higher baseline pain score and the higher placebo effect in knee compared to hip patients were only evident over the first dosing interval. The rate of placebo onset was faster in two studies investigating patients with more severe osteoarthritis (population not appropriate for NSAID use).
The placebo dropout pattern as well as the tanezumab dropout pattern was characterized for the first 3 doses separately using a parametric survival model.
An indirect response model was used to link the PK to WPS. The maximal achievable decrease in WPS by tanezumab was higher in females compared to males, higher in patients with OA of the hip and higher in patients with more severe pain at baseline. The potency of tanezumab was lower with higher baseline pain score and higher with higher body weight.
The simulations indicated the site of OA (knee or hip) to be the most potentially clinically relevant covariate for the clinical endpoint, followed by weight, baseline pain score and sex.
Conclusions: The established population PKPD model adequately describes the relationship between tanezumab concentration and WPS after IV administration in patients with OA. The most potentially clinically relevant covariate in terms of the endpoint is the site of OA. While other covariates predict additional small differences in the endpoint, all characterized groups gain benefit from treatment with tanezumab.