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"Samples spiked with a Factor Xa inhibitor in vitro. 'Mean ± SD of 10 samples/concentration.

'Calculated from species-specific control value. NA, not applicable.

"Samples spiked with a Factor Xa inhibitor in vitro. 'Mean ± SD of 10 samples/concentration.

'Calculated from species-specific control value. NA, not applicable.

all species. These ex vivo experiments demonstrated that the predicted efficacious dose of 0.2 to 0.3 |g/mL achieved the required 30 to 40% inhibition of FXa, providing early confidence in the dose selection process for phase I human trials. Additionally, these early ex vivo studies confirmed species-specific differences. The drug concentrations required to produce similar levels of FXa inhibition across species were markedly different. The FX:C assay was used effectively in preclinical rat and dog studies with this developmental FXa inhibitor. Knowledge of the species-specific concentration of drug required to induce the required 30% inhibition of FXa drove the selection of the low dose, whereas nearly complete inhibition of FXa drove the selection of the high dose. The FX:C assay helped determine the drug concentration required for complete inhibition of factor Xa in these species and the relative bleeding risk associated with a range of factor X concentrations. Prior knowledge of the impact of this drug on FXa inhibition through fairly simple clotting assessments helped eliminate undue risks of over-anticoagulation in preclini-cal studies, and there was no loss of animals due to excessive hemorrhage. It also addressed questions of whether dosing had been pushed to high enough levels when only minimal bleeding was observed at the highest dose. Since nearly 100% inhibition was achieved during the study, using higher doses was not indicated and the lack of bleeding under conditions of complete FXa inhibition in rats and dogs suggested a strong safety profile. Inclusion of these biomarkers in preclinical studies provided greater confidence for selection of target stopping criteria for the first-in-human trial. The FX:C assay was translated and used as part of the first-in-human clinical trial with this compound. The FX:C assay provided data consistent with in vitro modeling, suggesting that it is predictive of drug concentration.

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