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

BACKGROUND: 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. METHODS: 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. RESULTS: 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]. CONCLUSION: 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. TRIAL REGISTRATION: This trial was registered on www.ClinicalTrials.gov (NCT 04684732). Registration date was 2020-12-14.