Slow drug-target complex kinetics and first dose overestimation of free target suppression in target-mediated drug disposition (TMDD) approximation models: An evaluation for tanezumab a NGF antibody for treatment of pain
Satoshi Shoji (1), Scott Marshall (2), Rujia Xie (2), and Rosalin Arends (3)
(1) Pharmacometrics Pfizer Japan Inc. (2) Pharmacometrics Pfizer Inc. (3) Clinical Pharmacology Pfizer Inc.
Objectives: TMDD model approximations are useful in allowing estimation of alternative hybrid parameters when the full TMDD modelling is over parameterized [1-4]. For the NGF antibody tanezumab, the QSS TMDD approximation model was developed [5]. The free target (NGF) prediction suggested the approximation would overestimate the initial first dose free target suppression. Objectives of this study were to characterize the overestimation and to quantify the impact when varying the target binding parameter values.
Methods: Quasi-steady-state (QSS), Michaelis-Menten (MM), and indirect response (IR) approximation models were evaluated to confirm whether early overestimation existed. Parameters available from the previous model [5] and in-vitro Kd [6] value were used for this investigation. Impact of the overestimation was evaluated based on sensitivity analysis over the first 28 days following the first subcutaneous tanezumab administration. Metrics for the overestimation were root mean squared error (RMSE) reflecting absolute difference (pM) from full TMDD, relative %RMSE and %AUC ratio to full TMDD.
Results: Overestimation of the free target suppression existed and, as expected, was similar across QSS, MM, and IR models in our simulation settings. Higher complex production rate and/or elimination rates relative to drug-target complex rate (dRC/dt) were needed to reduce the overestimation. Sensitivity analysis showed increasing koff or kint ~ 6- to 7-fold or increasing both by ~ 4 fold relative to the tanezumab estimates reduced the overestimation to insignificant levels of %AUC (~ 20%). Increasing kon 2- to 20-fold progressively improved RMSE but did not improve %RMSE or %AUC indicating that with production rate already above the drug-target complex rate for tanezumab, a greater production rate due to a higher Kon value would further suppress NGF but have no impact on reducing the initial discrepancy between the full and TMDD approximation models.
Conclusions: Overestimation of free target suppression during the initial “fast phase” in TMDD approximation models is already known. This work illustrates approaches to determine the extent and duration of this difference, which could be important when predicting acute effects, such as the onset of analgesia, for drugs displaying TMDD.
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