Prospective dose prediction for FXa inhibitor otamixaban (OTAM) using PK/PD simulations accounting for non-dose proportional plasma exposure

Abstract

Background/Aims OTAM is a direct and selective FXa inhibitor under development for treatment of Acute Coronary Syndrome (ACS). This work describes PK/PD modeling and simulations to predict doses for dose-ranging Phase II study with target Ceoi of 75 to 600 ng/mL (MTD). Methods Plasma concentrations-time data from 3 Phase I/II studies were fitted simultaneously to a two-compartment model using WINNONLIN. The change in plasma clearance and volume of distribution with dose was accounted by introducing a linear equation for the change in volume of distribution as a function of the infusion rate. Furthermore, because a linear relationship exists between PK and PD clotting time markers (aPTT, PT, and RVVT), PK concentrations were sufficient to predict PD. Results Simulated mean concentrations were well separated for each dose. The combined 1 min/3 h infusions allowed target Ceoi to be reached immediately, with a “dip” not exceeding 20% of Ceoi. Conclusions Predictable PK/PD model allowed for optimal dose selection for the Phase II study. Figure 1. Download figure to PowerPoint (see Table) Clinical Pharmacology & Therapeutics (2005) 77, P40–P40; doi: 10.1016/j.clpt.2004.12.047 Table 1. Target Plasma Concentration ng/mL Dosage Predicted Plasma Concentration at Time Post- start of Infusion (ng/mL) Group Bolus mg/kg Infusion mg/kg/h 1 min 10 min 0.75 h 3 h 4 h 5 h 75 1 0.025 0.035 153 106 71 75 38 24 150 2 0.045 0.065 275 193 133 146 70 44 300 3 0.080 0.120 481 361 256 301 127 80 450 4 0.120 0.160 736 526 383 448 174 110 600 5 0.140 0.200 861 632 494 617 215 135