(T1130-09-52) A Modelling and Simulation Assessment of Steady State Apixaban Delivered from a Weekly Transdermal Patch

Purpose: Eliquis® (apixaban), is an effective oral anticoagulant for different indications¹ and is used twice daily in the therapy² administration. In order to support weekly apixaban transdermal delivery system, a modelling and simulation strategy was applied for the assessment of steady state attainment using various factors such as flux rate, patch size and presumed dermal bioavailability.

Methods: Previously published intravenous pharmacokinetic data of apixaban³ was used for modelling and simulations (M&S). The reported mean apixaban concentrations after IV administration were fitted using compartmental models with linear elimination. For the simulation of weekly apixaban transdermal patch the model was extended by an absorption model into the plasma compartment. The simulations (n=500 trials sampled from uncertainty) were performed with the following variables: dermal bioavailability (80% or 100%), differing flux rates (5, 6, 7, 8 and 9 µg/h/cm²) and patch sizes (4, 20, 30 cm²). The average steady state plasma exposure concentrations (C_avg) derived from the weekly apixaban patch, was compared to the published C_avg data at the oral therapeutic dose of 5 mg BID apixaban.⁴

Results: The data was best described by a 3-compartmental model. However, as the 2-compartmental model also described the data in the elimination phase equally well, both models were used for simulations providing similar results. The simulations suggested a gradual but rapid entry of apixaban from the weekly transdermal system into the systemic circulation (Figure 1). With higher flux rates, a higher attainment of exposures was observed. Furthermore, higher dermal bioavailability (100%) gave higher exposures as compared to 80% dermal bioavailability. The time to reach steady state from the weekly apixaban batch was independent of flux rate or bioavailability. Furthermore, 95% and 99% of steady-state concentration of apixaban was reached within ~1.5 days and ~3 days, respectively, from the transdermal delivery system. Overall, with the assumption of 100% bioavailability, a weekly patch sizes of 20 cm² and 30 cm² will deliver C_avg exposures of approximately ~54 and ~81 ng/mL, respectively. The data suggested that patch size of 30-40 cm² may be needed to deliver steady state C_avg eµxposure of apixaban comparable to that obtained from oral dosing of 5 mg BID apixaban to steady state (~87 ng/mL).

Conclusion: Modelling and simulation approach was implemented using the published pharmacokinetic data for apixaban and reasonable assumptions on fluxes, bioavailability and patch size for the transdermal administration. Simulations suggested that the transdermal delivery of apixaban would result in a gradual but rapid entry of apixaban with steady state of 95% and 99% achieved by 1.5 and 3 days, respectively. At a flux rate of approximately 7 µg/h/cm² a C_avg exposure of ~83 ng/mL was predicted. Based on the overall data, it can be concluded that approximately 30 – 40 cm² patch size at a 7 µg/h/cm² flux rate is required to attain a steady state equivalent C_avg exposure to that of oral RLD.

References: 1. Buckley BJR, Lane DA, Calvert P, Zhang J, Gent D, Mullins CD, Dorian P, Kohsaka S, Hohnloser SH, Lip GYH. Effectiveness and Safety of Apixaban in over 3.9 Million People with Atrial Fibrillation: A Systematic Review and Meta-Analysis. J Clin Med. 2022 Jun 30;11(13):3788. doi:10.3390/jcm11133788.
2. Byon W, Garonzik S, Boyd RA, Frost CE. Apixaban: A Clinical Pharmacokinetic and Pharmacodynamic Review. Clin Pharmacokinet. 2019 Oct;58(10):1265-1279. doi: 10.1007/s40262-019-00775-z.
3. Vakkalagadda B, Frost C, Byon W, Boyd RA, Wang J, Zhang D, Yu Z, Dias C, Shenker A, LaCreta F. Effect of Rifampin on the Pharmacokinetics of Apixaban, an Oral Direct Inhibitor of Factor Xa. Am J Cardiovasc Drugs. 2016 Apr;16(2):119-27. doi: 10.1007/s40256-015-0157-9.
4. Frost C, Nepal S, Wang J, Schuster A, Byon W, Boyd RA, Yu Z, Shenker A, Barrett YC, Mosqueda-Garcia R, Lacreta F. Safety, pharmacokinetics and pharmacodynamics of multiple oral doses of apixaban, a factor Xa inhibitor, in healthy subjects. Br J Clin Pharmacol. 2013 Nov;76(5):776-86. doi: 10.1111/bcp.12106

Figure 1: Predicted mean concentrations of apixaban using a 3-compartment model from a weekly transdermal delivery system based on selected patch size, bioavailability and flux rate (F: Bioavailability Patch flux assumed to be 7 µg/h/cm2, Line and shades indicate median and 90% CI determined based on 500 simulations with parameters sampled from uncertainty)