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Quantification of Apixaban's Therapeutic Utility in Prevention of Venous Thromboembolism: Selection of Phase III Trial Dose
Author(s) -
Leil T A,
Feng Y,
Zhang L,
Paccaly A,
Mohan P,
Pfister M
Publication year - 2010
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1038/clpt.2010.106
Subject(s) - apixaban , medicine , regimen , warfarin , therapeutic index , venous thromboembolism , renal function , pharmacology , clinical trial , odds ratio , urology , rivaroxaban , drug , atrial fibrillation , thrombosis
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 µg·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. Clinical Pharmacology & Therapeutics (2010) 88 3, 375–382. doi: 10.1038/clpt.2010.106