Key result
PBPK modeling of rivaroxaban with concomitant erlotinib or nilotinib indicated that dose reductions from 20 to 15 and 10 mg in normal and mild renal dysfunction, respectively, are warranted.
Why the study?
Rivaroxaban's multiple elimination pathways predispose it to drug-drug-disease interactions with protein kinase inhibitors in cancer-associated venous thromboembolism, prompting prospective interrogation for dose adjustments.
Does concomitant use of protein kinase inhibitors (erlotinib and nilotinib) alter rivaroxaban exposure requiring dose adjustments in cancer-associated VTE?
Does concomitant use of protein kinase inhibitors (erlotinib and nilotinib) alter rivaroxaban exposure requiring dose adjustments in cancer-associated VTE?
PBPK modeling indicates that rivaroxaban doses should be reduced when co-administered with erlotinib or nilotinib in patients with cancer-associated VTE to mitigate bleeding risks.
May warrant rivaroxaban dose adjustment with these TKIs; hypothesis-generating pending clinical validation.
Aims Rivaroxaban is a viable anticoagulant for the management of cancer‐associated venous thromboembolism (CA‐VTE). A previously verified physiologically‐based pharmacokinetic (PBPK) model of rivaroxaban established how its multiple pathways of elimination via both CYP3A4/2J2‐mediated hepatic metabolism and organic anion transporter 3 (OAT3)/P‐glycoprotein‐mediated renal secretion predisposes rivaroxaban to drug–drug–disease interactions (DDDIs) with clinically relevant protein kinase inhibitors (PKIs). We proposed the application of PBPK modelling to prospectively interrogate clinically significant DDIs between rivaroxaban and PKIs (erlotinib and nilotinib) for dose adjustments in CA‐VTE. Methods The inhibitory potencies of the PKIs on CYP3A4/2J2‐mediated metabolism of rivaroxaban were characterized. Using prototypical OAT3 inhibitor ketoconazole, in vitro OAT3 inhibition assays were optimized to ascertain the in vivo relevance of derived transport inhibitory constants ( K i ). Untested DDDIs between rivaroxaban and erlotinib or nilotinib were simulated. Results Mechanism‐based inactivation (MBI) of CYP3A4‐mediated rivaroxaban metabolism by both PKIs and MBI of CYP2J2 by erlotinib were established. The importance of substrate specificity and nonspecific binding to derive OAT3‐inhibitory K i values of ketoconazole and nilotinib for the accurate prediction of interactions was illustrated. When simulated rivaroxaban exposure variations with concomitant erlotinib and nilotinib therapy were evaluated using published dose–exposure equivalence metrics and bleeding risk analyses, dose reductions from 20 to 15 and 10 mg in normal and mild renal dysfunction, respectively, were warranted. Conclusion We established a PBPK‐DDDI model to prospectively evaluate clinically relevant interactions between rivaroxaban and PKIs for the safe and efficacious management of CA‐VTE.
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Cheong et al. (2021) studied Cancer-associated venous thromboembolism (CA-VTE). Rivaroxaban with concomitant erlotinib or nilotinib was evaluated on Simulated rivaroxaban exposure variations and bleeding risk. PBPK modeling of rivaroxaban with concomitant erlotinib or nilotinib indicated that dose reductions from 20 to 15 and 10 mg in normal and mild renal dysfunction, respectively, are warranted.
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