title: Quantification of apixaban's therapeutic utility in prevention of venous thromboembolism: selection of phase III trial dose.
abstract: A model-based approach was used to integrate data from a phase II study in order to provide a quantitative rationale for selecting the apixaban dosage regimen for a phase III trial. The exposure-response models demonstrated that an increase in daily steady-state area under the plasma concentration-vs.-time curve (AUC(ss)) of 1 microg x h/ml would increase the odds ratio for major bleeding by 0.118 and decrease the odds ratio for venous thromboembolism (VTE) by 0.0499. The therapeutic utility index (TUI) was used to integrate the efficacy and safety predictions to quantify apixaban's efficacy/safety balance as a function of AUC(ss). Of the apixaban dosage regimens tested in phase II, the 2.5 mg twice-daily (b.i.d.) dosage regimen had the highest TUI (86.2%). This was also higher than the TUI for either 30 mg b.i.d. enoxaparin (82.5%) or for warfarin (71.8%). Subjects with moderate renal impairment are expected to have a 43% increase in apixaban exposure; however, apixaban's TUI suggests that dose adjustment is not needed in these subjects with renal impairment.
authors.affiliation: Discovery Medicine and Clinical Pharmacology, Bristol-Myers Squibb, Lawrenceville, New Jersey, USA. tarek.leil@pfizer.com
authors.forename: T A
authors.initials: TA
authors.lastname: Leil
authors.forename: Y
authors.initials: Y
authors.lastname: Feng
authors.forename: L
authors.initials: L
authors.lastname: Zhang
authors.forename: A
authors.initials: A
authors.lastname: Paccaly
authors.forename: P
authors.initials: P
authors.lastname: Mohan
authors.forename: M
authors.initials: M
authors.lastname: Pfister
mesh_terms: D000368:Aged; D019540:Area Under Curve; D017322:Clinical Trials, Phase II as Topic; D017326:Clinical Trials, Phase III as Topic / Q000379:methods; D003198:Computer Simulation; D004305:Dose-Response Relationship, Drug; D017984:Enoxaparin / Q000008:administration & dosage / Q000494:pharmacology; D005260:Female; D005343:Fibrinolytic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D006470:Hemorrhage / Q000139:chemically induced*; D006801:Humans; D007674:Kidney Diseases / Q000150:complications; D008297:Male; D008954:Models, Biological; D011720:Pyrazoles / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D011728:Pyridones / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D054556:Venous Thromboembolism / Q000517:prevention & control*; D014859:Warfarin / Q000008:administration & dosage / Q000494:pharmacology
chemical_list: D017984:Enoxaparin; D005343:Fibrinolytic Agents; D011720:Pyrazoles; D011728:Pyridones; C522181:apixaban; D014859:Warfarin