In Vitro Assessment of Pharmacokinetic Drug-Drug Interactions of Direct Oral Anticoagulants: Type 5-Phosphodiesterase Inhibitors Are Inhibitors of Rivaroxaban and Apixaban Efflux by P-Glycoprotein

Abstract

Because of their lower bleeding risk and simplicity of use, direct oral anticoagulants (DOACs) could represent an interesting alternative to conventional anticoagulant treatment with vitamin K antagonists for patients with pulmonary arterial hypertension (PAH). P-glycoprotein (P-gp) plays a key role in DOAC pharmacokinetics. Type 5-phosphodiesterase inhibitors (PDE5is), a drug class commonly used in the treatment of PAH, have been shown to strongly inhibit P-gp. This work aimed to assess potential P-gp-mediated drug-drug interactions between PDE5is and DOACs using in vitro methods. A cellular model of drug transport assay, using P-gp-overexpressing Madin-Darby canine kidney cells (transfected with the human P-gp gene), was used to determine the bidirectional permeabilities of two DOACs (rivaroxaban and apixaban) in the absence and presence of increasing concentrations (0.5-100 M) of three PDE5is (sildenafil, tadalafil, and vardenafil). Permeabilities and efflux ratios were calculated from DOAC concentrations, were measured with liquid chromatography coupled with mass spectrometry, and were subsequently used to determine the PDE5i percentage of inhibition and half maximal inhibitory concentration (IC ). Rivaroxaban efflux was inhibited by 99%, 66%, and 100% with 100 M sildenafil, tadalafil, and vardenafil, respectively. Similarly, apixaban efflux was inhibited by 97%, 74%, and 100%, respectively. The IC values of the three PDE5is were 8, 28, and 5 M for rivaroxaban and 23, 15, and 3M for apixaban, respectively. This study showed strong in vitro inhibition of DOAC efflux by PDE5is. In vivo studies are required to determine the clinical relevance of these interactions.

Drug interactions with apixaban: A systematic review of the literature and an analysis of VigiBase, the World Health Organization database of spontaneous safety reports

“…In another in vitro study performed by Margelidon‐Cozzolino et al, three PDE5 inhibitors (sildenafil, tadalafil, and vardenafil) strongly inhibited apixaban efflux by P‐gp suggesting potential clinically relevant DDI 29 . The maximal inhibition was higher with vardenafil and sildenafil than with tadalafil 29 …”

Use of Anticoagulants in Patients with Pulmonary Hypertension

“…63 This may be explained by pharmacological issues between DOACs and the targeted PAH drugs, as some of them (bosentan, phosphodiesterase-5 inhibitors, riociguat) may provide significant drug-drug interaction with DOACs. [64][65][66] Hence, a modified bioaccumulation of DOACs in patients receiving treatment for PAH or CTEPH may be part of the absence of better safety compared with VKAs. In terms of efficacy, it has been demonstrated that VTE recurrence may be an explanation of PH recurrence after surgery, 67 highlighting the need for a highly efficient therapy.…”

Direct oral anticoagulants: Still too early for prime time after pulmonary endarteriectomy?

“…5 Moreover, a significant major drug-drug interaction (DDI) has been observed between DOACs and Type 5-Phosphodiesterase inhibitors, a major drug class in pulmonary arterial hypertension treatment. 6 Even if DOACs are associated with a decreased risk of major bleeding, such DDI may counterbalance this safety benefit, via the inhibition of P-glycoprotein.…”