title: Model-based exposure-response analysis of apixaban to quantify bleeding risk in special populations of subjects undergoing orthopedic surgery.
abstract: Population pharmacokinetic (PK) and exposure-response analyses of apixaban were performed using data from phase I-III studies to predict bleeding risks for patients receiving apixaban 2.5 mg b.i.d. after total knee or hip replacement (TKR, THR) surgery (N = 5,510). Renal function, age, gender, and body weight impacted apixaban exposure. Bleeding risk increased as a function of exposure. Predicted bleeding frequencies for TKR and THR populations at risk for high apixaban exposure (female, age > 75 years, calculated creatinine clearance (cCrCL) < 30 ml/min, body weight < 50 kg) (6.85 and 10.3%, respectively) were comparable to the reference population (male/female, age 65-75 years, cCrCL ≥ 80 ml/min, body weight 65-85 kg) (6.18 and 9.32%, respectively). A 100% increase in apixaban exposure is expected to raise bleeding frequencies to 7.25% (TKR) and 10.9% (THR), whereas a 200% increase would raise them to 8.49 and 12.7%. Coexistence of combined patient risk factors or doubling of exposure is not likely to result in a substantial, clinically relevant increase in bleeding risk with 2.5 mg b.i.d. apixaban.
authors.affiliation: Bristol-Myers Squibb Company, Princeton, New Jersey, USA.
authors.forename: T A
authors.initials: TA
authors.lastname: Leil
authors.affiliation: Bristol-Myers Squibb Company, Princeton, New Jersey, USA.
authors.forename: C
authors.initials: C
authors.lastname: Frost
authors.affiliation: Bristol-Myers Squibb Company, Princeton, New Jersey, USA.
authors.forename: X
authors.initials: X
authors.lastname: Wang
authors.affiliation: 1] Bristol-Myers Squibb Company, Princeton, New Jersey, USA [2] Current address: Quantitative Solutions, Inc., Menlo Park, CA, USA; and University Children's Hospital Basel, University of Basel, Basel, Switzerland.
authors.forename: M
authors.initials: M
authors.lastname: Pfister
authors.affiliation: Bristol-Myers Squibb Company, Princeton, New Jersey, USA.
authors.forename: F
authors.initials: F
authors.lastname: LaCreta