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This information is intended for US healthcare professionals to access current scientific information about J&J Innovative Medicine products. It is prepared by Medical Information and is not intended for promotional purposes, nor to provide medical advice.

UPTRAVI® (selexipag)

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UPTRAVI - Drug-Drug and Pharmacokinetic Interaction Studies

Last Updated: 09/13/2024

SUMMARY

Concomitant administration of UPTRAVI with gemfibrozil, a strong inhibitor of cytochrome P450 (CYP) 2C8 doubled exposure to selexipag and increased exposure to the active metabolite by approximately 11-fold.¹
Concomitant administration of UPTRAVI with clopidogrel, moderate inhibitor of CYP2C8, had no relevant effect on the exposure to selexipag and increased the exposure to the active metabolite by approximately 2.7-fold after maintenance doses of clopidogrel. It is recommended to reduce the dose of UPTRAVI to once daily.²
Concomitant administration with an inducer of CYP2C8 and uridine 5’-diphospho-glucuronosyltransferase (UGT) 1A3 and 2B7 enzymes (rifampin) halved exposure to the active metabolite. Increase dose up to twice of UPTRAVI when co-administered with rifampin. It is recommended to reduce the dose of UPTRAVI when rifampin is stopped.¹
No dose adjustment is recommended with warfarin, lopinavir/ritonavir, midazolam, endothelin receptor antagonists (ERAs), phosphodiesterase-5 inhibitors (PDE-5i), or ERAs plus PDE-5i.³^,⁴
Additional information for review is provided in the REFERENCES.⁵^,⁶

CLINICAL DATA

Key Phase I Studies

Please refer to the Table: Phase I Selexipag Studies for key phase I selexipag studies related to drug-drug interaction, pharmacokinetics (PK)/pharmacodynamics (PD) and special populations.

Phase I Selexipag Studies

Study ID	Objectives	Key Results
QGUY-B⁷	Interaction with food	Tolerability may be improved when taken with food
QGUY-D³	DDI: Warfarin	No dose adjustment of UPTRAVI or warfarin recommended
AC-065-104⁸	Tolerability and safety in mild, moderate and severe hepatic impairment (Child-Pugh Class A, B and C, respectively)	Mild: No dosage adjustment requirement Moderate: Increased exposure to selexipag and its active metabolite requiring dose adjustment^a Severe: No data available
AC-065-105⁸	Tolerability and safety in severe renal impairment	No dose adjustment needed with eGFR down to 15 mL/min/1.73 m²
Administration, distribution, metabolism, excretion⁹	Rate and routes of elimination, PK, tolerability	Approximately 93% of drug material excreted in the feces, 12% in the urine Neither selexipag nor its active metabolite found in urine
AC-065-106¹⁰	QTc interval	No effect on cardiac repolarization
AC-065-109⁴	DDI: Kaletra^® (lopinavir/ritonavir)	No dose adjustment recommended
AC-065-113¹	DDI: Lopid^® (gemfibrozil) DDI: Rifadin^® (rifampicin)	Gemfibrozil, a strong inhibitor of CYP2C8, increased the exposure to ACT-333679 by approximately 11-fold Rifampicin, a moderate inducer of CYP2C8, reduced the exposure to ACT-333679 by approximately 50%
AC-065-114¹¹	DDI: Versed^® (midazolam)	Exposure to midazolam and 1-hydroxymidazolam was not affected
AC-065-117²	DDI: Plavix^® (clopidogrel bisulfate)	Clopidogrel, a strong inhibitor of CYP2C8, increased the exposure to ACT-333679 after a loading dose of clopidogrel (300 mg) by approximately 2.2-fold Clopidogrel, a strong inhibitor of CYP2C8, increased the exposure to ACT-333679 after maintenance doses of clopidogrel (75 mg QD) by approximately 2.7-fold
Abbreviations: CYP, cytochrome P450; DDI, drug-drug interaction; eGFR, estimated glomerular filtration rate; PK, pharmacokinetics; QTc, corrected QT interval; QD, daily.

Literature Search

A literature search of MEDLINE^®, Embase^®, BIOSIS Previews^®, Derwent Drug File (and/or other resources, including internal/external databases) was conducted on 28 August 2024.

References

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1	Bruderer S, Petersen-Sylla M, Boehler M, et al. Effect of gemfibrozil or rifampicin on the pharmacokinetics of selexipag and its active metabolite in healthy subjects. Br J Clin Pharmacol. 2017;83(12):2778-2788.
2	Axelsen L, Poggesi I, Rasschaert F, et al. Clopidogrel, a CYP2C8 inhibitor, causes a clinically relevant increase in the systemic exposure to the active metabolite of selexipag in healthy subjects. Br J Clin Pharmacol. 2021;87(1):119-128.
3	Bruderer S, Okubo K, Mukai H, et al. Investigation of Potential Pharmacodynamic and Pharmacokinetic Interactions Between Selexipag and Warfarin in Healthy Male Subjects. Clin Ther. 2016;38(5):1228-1236.e1.
4	Kaufmann P, Niglis S, Bruderer S, et al. Effect of lopinavir/ritonavir on the pharmacokinetics of selexipag an oral prostacyclin receptor agonist and its active metabolite in healthy subjects. Br J Clin Pharmacol. 2015;80(4):670-677.
5	Katayama N, Odagiri K, Hakamata A, et al. Clinical evaluation of drug-drug interactions between the cytochrome P450 substrates selexipag and clopidogrel in Japanese volunteers. Br J Clin Pharmacol. 2021;87(4):1903-1911.
6	Küçükosmanoglu A, Scoarta S, Houweling M, et al. A real-world toxicity atlas shows that adverse events of combination therapies commonly result in additive interactions. Clin Cancer Res. 2024;30(8):OF1-OF11.
7	Kaufmann P, Okubo K, Bruderer S, et al. Pharmacokinetics and tolerability of the novel oral prostacyclin IP receptor agonist selexipag. Am J Cardiovasc Drugs. 2015;15(3):195-203.
8	Kaufmann P, Cruz HG, Krause A, et al. Pharmacokinetics of the novel oral prostacyclin receptor agonist selexipag in subjects with hepatic or renal impairment. Br J Clin Pharmacol. 2016;82(2):369-379.
9	Kaufmann P, Okubo K, Sidharta P, et al. Investigation of the absorption, metabolism, and excretion of 14C-selexipag following administration to healthy male subjects. Poster presented at: American Society for Clinical Pharmacology and Therapeutics (ASCPT); March 14-17, 2012; National Harbor, MD.
10	Hoch M, Darpo B, Remenova T, et al. A thorough QT study in the context of an uptitration regimen with selexipag, a selective oral prostacyclin receptor agonist. Drug design, development and therapy. 2015;9:175-185.
11	Juif PE, Boehler M, Donazzolo Y, et al. A pharmacokinetic drug-drug interaction study between selexipag and midazolam, a CYP3A4 substrate, in healthy male subjects. Eur J Clin Pharmacol. 2017;73(9):1121-1128.