Author + information
- Eleanor Jing Yi Cheong, BScPharm,
- Janice Jia Ni Goh, BScPharm,
- Yanjun Hong, PhD,
- Pipin Kojodjojo, MBBS, PhD and
- Eric Chun Yong Chan, PhD∗ ()
- ↵∗Department of Pharmacy, Faculty of Science, National University of Singapore, 18 Science Drive 4, Singapore 117543, Singapore
Rivaroxaban undergoes hepatic metabolism by cytochrome P450 (CYP) enzymes (CYP3A4 and CYP2J2) and renal excretion via P-glycoprotein (P-gp)–mediated secretion (1). Amiodarone and its main metabolite N-desethylamiodarone (NDEA) inhibit CYP3A4 (irreversibly and reversibly) and P-gp when rivaroxaban is the substrate (2). Here, we simulated prospective drug–drug interactions (DDIs) between rivaroxaban and amiodarone using physiologically-based pharmacokinetic (PBPK) modeling and recommended dose adjustments in renal impairment.
All PBPK modeling and simulations were performed and verified using Simcyp (V. 15, Sheffield, United Kingdom). The PBPK model of rivaroxaban was constructed by incorporating physicochemical properties, in vitro metabolism data, and clinical pharmacokinetic (PK) parameters. PBPK models of amiodarone and N-desethylamiodarone were adopted from verified data (3). Simulations of DDIs between rivaroxaban and amiodarone were based on the 2014 American Heart Association/American College of Cardiology/Heart Rhythm Society Guideline for the Management of Patients with Atrial Fibrillation (4). Changes to the area under the plasma concentration time curve (AUC) of 20 mg rivaroxaban daily were investigated in 100 healthy male participants (age 20 to 55 years) during both the loading and maintenance phases of amiodarone. The influences of age (65 to 78 years) based on population demographics in the ROCKET AF (Rivaroxaban versus Warfarin in Nonvalvular Atrial Fibrillation) trial (5), as well as mild (creatinine clearance [CrCL] 50 to 79 ml/min) and moderate (CrCL 30 to 49 ml/min) renal impairment (RI) on the postulated DDIs were also evaluated. As rivaroxaban yields linear PK up to 20 mg daily doses with food, the simulated AUCrivaroxaban with amiodarone/AUCrivaroxaban in healthy control subjects was used as the reduction factor for dose adjustment.
The developed PBPK model facilitated quantitative reproduction of PK data following single 10- and 20-mg doses of rivaroxaban under fasting/fed conditions and demonstrated a lack of accumulation upon multiple dosing. Retrospective DDI simulations with erythromycin and ketoconazole confirmed the fractional contribution of CYP3A4, CYP2J2, and P-gp–mediated clearance to rivaroxaban’s elimination. Accurate recapitulation of the effect of steady state erythromycin on rivaroxaban’s systemic exposure in chronic kidney disease populations further affirmed the predictive potential of the PBPK model of rivaroxaban and increased confidence in subsequent predictions of unexplored interactions with amiodarone.
The systemic exposure of rivaroxaban (20 mg once daily, days 1 to 20) was increased when coadministered with loading doses of amiodarone 200 mg 3× daily (days 5 to 20) in healthy subjects, with a simulated mean AUC-fold change of 1.36 (95% confidence interval [CI]: 1.23 to 1.50). Based on the pre-defined dose exposure equivalence of 0.70 to 1.43 in a population PK study and current rivaroxaban interaction guidelines, the extent of DDI is not clinically significant (Figure 1). Conversely, the combined effects of amiodarone and mild RI produced a clinically significant increase in rivaroxaban exposure, with a simulated mean AUC-fold change of 1.86 (95% CI: 1.68 to 2.06). Simulations also indicated a significant increase in mean AUC of 1.61-fold (95% CI: 1.45- to 1.78-fold) in moderate RI where a stipulated reduced rivaroxaban dose of 15 mg was utilized. The effect of age potentiated the extent of interaction across mild and moderate RI with mean AUC-fold changes of 2.40 (95% CI: 2.15 to 2.62) and 2.07 (95% CI: 1.86 to 2.30) respectively.
Given that age and renal insufficiency produced clinically significant increases in rivaroxaban exposure with amiodarone coadministration, dosing adjustments were investigated considering the linear PK of rivaroxaban up to 20 mg under fed conditions. Revised rivaroxaban doses of 10 mg mitigated the effects of DDIs, yielding systemic exposures of rivaroxaban comparable to those achieved at the therapeutic 20 mg dose in young and elderly subjects with mild and moderate RI (Figure 1).
Current guidelines discourage the concomitant use of combined P-gp and moderate CYP3A4 inhibitors with rivaroxaban in patients with CrCL 15 to <80 ml/min, severely hampering clinically relevant combinations. With systematic PBPK-guided dose reduction of rivaroxaban in the presence of concomitant amiodarone, the extent of pharmacokinetic DDIs is minimized while anticoagulant efficacy is likely preserved, making it possible to extend pharmacotherapy across a wider spectrum of patient subgroups.
Please note: This study was funded by the Singapore Ministry of Education (MOE) Funding (Grant Number R-148-000-249-114). The authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- 2018 American College of Cardiology Foundation
- Weinz C.,
- Schwarz T.,
- Kubitza D.,
- et al.
- Cheong E.J.Y.,
- Goh J.J.N.,
- Hong Y.,
- et al.
- Chen Y.,
- Mao J.,
- Hop C.E.C.A.
- January C.T.,
- Wann L.S.,
- Alpert J.S.,
- et al.