The metabolism and drug–drug interaction potential of the selective prostacyclin receptor agonist selexipag

Abstract

1. The metabolism of selexipag has been studied in vivo in man and the main excreted metabolites were identified. Also, metabolites circulating in human plasma have been structurally identified and quantified. 2. The main metabolic pathway of selexipag in man is the formation of the active metabolite ACT-333679. Other metabolic pathways include oxidation and dealkylation reactions. All primary metabolites undergo subsequent hydrolysis of the sulphonamide moiety to their corresponding acids. ACT-333679 undergoes conjugation with glucuronic acid and aromatic hydroxylation to P10, the main metabolite detected in human faeces. 3. The formation of the active metabolite ACT-333679 is catalysed by carboxylesterases, while the oxidation and dealkylation reactions are metabolized by CYP2C8 and CYP3A4. CYP2C8 is the only P450 isoform catalysing the aromatic hydroxylation to P10. CYP2C8 together with CYP3A4 are also involved in the formation of several minor ACT-333679 metabolites. UGT1A3 and UGT2B7 catalyse the glucuronidation of ACT-333679. 4. The potential of selexipag to inhibit or induce cytochrome P450 enzymes or drug transport proteins was studied in vitro. Selexipag is an inhibitor of CYP2C8 and CYP2C9 and induces CYP3A4 and CYP2C9 in vitro. Also, selexipag inhibits the transporters OATP1B1, OATP1B3, OAT1, OAT3, and BCRP. However, due to its low dose and relatively low unbound exposure, selexipag has a low potential for causing drug-drug interactions.

<p>Selexipag in the management of pulmonary arterial hypertension: an update</p>

“…Also, selexipag inhibits the transporters OATP1B1, OATP1B3, OAT1, OAT3, and BCRP. However, due to its relatively low unbound exposure at clinically used doses, selexipag has a low potential for causing drug–drug interactions 55. As expected, selexipag has no effect on warfarin levels56 and no significant interaction with the CYP3A4 metabolized midazolam 57.…”

Clopidogrel, a CYP2C8 inhibitor, causes a clinically relevant increase in the systemic exposure to the active metabolite of selexipag in healthy subjects

“…22,23 In contrast, gemfibrozil has been found to cause an increase in the AUC of simvastatin and simvastatin acid of 1.35-fold and 2.85-fold, respectively. 24 Selexipag and its active metabolite, ACT-333679, are substrates of CYP2C8 8 and OATP1B1/OATP1B3 10 in vitro. In 1 of our previous DDI studies, gemfibrozil increased the AUC of selexipag and ACT-333679 by 2-fold and 11-fold, respectively.…”

“…8,10,12 In addition, ACT-333679 is also metabolised by the uridine 5 0 -diphospho-glucuronosyltransferase (UGT) enzymes, UGT1A3 and UGT2B7. 8 In vitro, organic aniontransporting polypeptide (OATP) 1B1 and OATP1B3 are involved in the disposition of selexipag and ACT-333679. 8,10 The breast cancer resistance protein is also involved in the disposition of ACT-333679, whereas only selexipag is a substrate of P-glycoprotein.…”

“…ACT‐333679 is therefore considered to be the major contributor to the pharmacological effect. Both selexipag and ACT‐333679 are mainly excreated via hepatic clearance and metabolized by the cytochrome P450 (CYP) enzyme, CYP2C8, and to a lesser extent by CYP3A4 8,10,12 . In addition, ACT‐333679 is also metabolised by the uridine 5′‐diphospho‐glucuronosyltransferase (UGT) enzymes, UGT1A3 and UGT2B7 8 .…”

Clinical evaluation of drug–drug interactions between the cytochrome P450 substrates selexipag and clopidogrel in Japanese volunteers

“…Organic anion transporting polypeptide (OATP) 1B1 and OAPT1B3 also participate in their disposition. 9 Because both selexipag and ACT-333679 are mainly excreted via hepatic clearance, the exposure to selexipag and ACT-333679 is increased in patients with hepatic impairment. 10 Both selexipag and ACT-333679 bind selectively with high affinity to the IP receptor.…”