Format

Send to

Choose Destination
Drug Metab Dispos. 2019 Sep 10. pii: dmd.119.086918. doi: 10.1124/dmd.119.086918. [Epub ahead of print]

Systematic Development and Verification of A Physiologically-Based Pharmacokinetic Model of Rivaroxaban.

Author information

1
National University of Singapore.
2
National University of Singapore phaccye@nus.edu.sg.

Abstract

Rivaroxaban is indicated for stroke prevention in nonvalvular atrial fibrillation (AF). Its elimination is mediated by both hepatic metabolism and renal excretion. Consequently, its clearance is susceptible to both intrinsic (pathophysiological) and extrinsic (concomitant drugs) variabilities that in turn implicate bleeding risks. Upon systematic model verification, physiologically-based pharmacokinetic (PBPK) models are qualified for the quantitative rationalization of complex drug-drug-disease interactions (DDDIs). Hence, this study aimed to develop and verify a PBPK model of rivaroxaban systematically. Key parameters required to define rivaroxaban's disposition were either obtained from in vivo data or generated via in vitro transport kinetic assays. Our developed PBPK model successfully predicted rivaroxaban's clinical PK parameters within predefined success metrics. Consideration of basolateral organic anion transporter (OAT) 3-mediated proximal tubular uptake in tandem with apical P-glycoprotein (P-gp)-mediated efflux facilitated mechanistic characterization of the renal elimination of rivaroxaban in both healthy and renal impaired patients. Retrospective drug-drug interaction (DDI) simulations, incorporating in vitro metabolic inhibitory parameters, accurately recapitulated clinically observed attenuation of rivaroxaban's hepatic clearance due to enzyme-mediated DDIs with CYP3A4/2J2 inhibitors (verapamil and ketoconazole). Notably, transporter-mediated DDI simulations between rivaroxaban and P-gp inhibitors (verapamil and ketoconazole) yielded minimal increases in rivaroxaban's systemic exposure when P-gp-mediated efflux was solely inhibited. Subsequently, the arcane yet pivotal role of concomitant basolateral uptake inhibition in defining the clinically observed DDI magnitude was illuminated. In conclusion, our developed PBPK model of rivaroxaban is robustly verified for prospective interrogation and management of untested yet clinically relevant DDDIs pertinent to AF management. SIGNIFICANCE STATEMENT: Rivaroxaban is susceptible to drug-drug-disease interactions (DDDIs) comprising renal impairment, P-gp and CYP3A4/2J2 inhibition. Here, systematic construction and verification of a PBPK model of rivaroxaban, with the inclusion of a mechanistic kidney component, provided insight into the previously arcane role of OAT3-mediated basolateral uptake in influencing both clinically-observed renal elimination of rivaroxaban and differential extents of transporter-mediated DDIs. The verified model holds potential for investigating clinically-relevant DDDIs involving rivaroxaban and designing dosing adjustments to optimize its pharmacotherapy in atrial fibrillation.

KEYWORDS:

Transporter-mediated drug/metabolite disposition; Uptake transporters (OATP, OAT, OCT, PEPT, MCT, NTCP, ASBT, etc.); cytochrome P450; drug-drug interactions; efflux transporters (P-gp, BCRP, MRP, MATE, BSEP, etc); enzyme inactivation/mechanism-based inhibition; enzyme inhibitors; in vitro-in vivo prediction (IVIVE); modeling and simulation; physiologically-based pharmacokinetic modeling/PBPK

PMID:
31506301
DOI:
10.1124/dmd.119.086918
Free full text

Supplemental Content

Full text links

Icon for HighWire
Loading ...
Support Center