Dose Selection of Antithrombin (Recombinant) for a Phase 3 Trial in Early-Onset Preeclampsia [149].

INTRODUCTION: Acquired antithrombin deficiency is one of the distinguishing features of early-onset preeclampsia, the leading cause of maternal and perinatal morbidity and mortality. Antithrombin's pleiotropic effects suggest it may slow the progression of early-onset preeclampsia and extend pregnancy in patients being managed expectantly. Prior human studies demonstrate that maternal administration of antithrombin prolongs expectant management, but the source of antithrombin, human plasma, limits its use for early-onset preeclampsia. A multicenter, randomized, placebo-controlled, double-blind, phase 3 trial, PRESERVE-1, was designed to examine recombinant human antithrombin for early-onset preeclampsia. Because recombinant human antithrombin has different pharmacokinetic properties than human plasma antithrombin, population pharmacokinetic modeling was used to derive the optimal dose of recombinant human antithrombin for PRESERVE-1.

METHODS: Population pharmacokinetic modeling derived the area under the curve (AUC) of antithrombin activity from 3 to 7 days of once-a-day human plasma antithrombin bolus in two published preeclampsia clinical studies. A population pharmacokinetic model was developed from pregnant patients with hereditary antithrombin deficiency treated with recombinant human antithrombin. The effect of several recombinant human antithrombin dosing regimens on antithrombin activity levels and resulting AUCs in pregnant women were simulated.

RESULTS: A recombinant human antithrombin loading dose of 250 mg followed by continuous infusion of 2,000 mg per day provided the best dosing regimen to match exposure to an antithrombin activity range derived from prior human plasma antithrombin trials. This dosing regimen is currently tested in PRESERVE-1.

CONCLUSION AND IMPLICATION: By matching exposure from two human plasma antithrombin studies, similar efficacy may be obtained with recombinant human antithrombin. Efficacy may be improved by extending duration of recombinant human antithrombin treatment to delivery, as used in PRESERVE-1, instead of limiting treatment to 3-7 days in prior trials with human plasma antithrombin.