Development of a limited sampling strategy for apixaban area under the curve estimation in elderly patients with non-valvular atrial fibrillation

Pharmacokinetics (PK) and pharmacodynamics (PD) information of apixaban, a direct oral anticoagulant which is widely used for stroke prevention in elderly patients with non-valvular atrial fibrillation (NVAF), is scarce. This study aimed to characterize PK and anti-Xa activity of the drug and to develop a limited sampling strategy (LSS) for estimating the area under the apixaban concentration over 12-hour curve (AUC) in elderly patients with NVAF. Twenty-one Thai elderly patients receiving a stable apixaban dose of either 2.5 mg twice daily or 5 mg twice daily were enrolled. Venous blood samples were collected at pre-dose and 1, 2, 3, 4, 6, 9, and 12 h after dose for measuring plasma concentrations and anti-Xa activity of apixaban by a chromogenic anti-Xa assay. Measured 12-hour AUC (AUCm) was computed by linear trapezoidal rule. LSS equations were developed using stepwise multiple regression analysis. Predictive performance of the equations was assessed. The geometric mean (coefficient of variation) of minimum plasma concentration and AUCm were 87 (41%) ng/mL and 1,427 (36%) ng*hr/mL for the 5 mg dose, and 67 (56%) ng/mL and 1,049 (40%) ng*hr/mL for the 2.5 mg dose, respectively. High inter-patient variability of PK and PD of apixaban was detected. Predicted AUC calculated from the two-point LSS model using pre-dose concentration and 4-hour post-dose concentration (predicted AUC = 50 + 7(C0) + 5(C4)) correlates well with AUCm (adjusted R2 = 0.931, p < 0.001) with median percentage prediction error of -1% [5th to 95th percentile: -16 to 27] and median absolute percentage prediction error of 7% [5th to 95th percentile: 0 to 27]. High inter-patient variability of PK and PD of apixaban was demonstrated. The developed and internally validated LSS offers a practical approach for therapeutic drug monitoring and individualizing of apixaban treatment for elderly patients. This trial was registered on www.ClinicalTrials.gov (NCT 04684732). Registration date was 2020-12-14.