Contribution of Human Liver and Intestinal Carboxylesterases to the Hydrolysis of Selexipag In Vitro

Imai, Shunji; Ichikawa, Tomohiko; Sugiyama, Chihiro; Nonaka, Kiyoko; Yamada, Tetsuhiro

doi:10.1016/j.xphs.2018.09.022

Cited by 11 publications

(6 citation statements)

References 28 publications

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“… 2019 ; Imai et al. 2019 ). It is recommended that the initial dose of selexipag is 200 μg twice daily, and it can be increased to a maximum dose of 1600 μg twice daily based on the individual patient’s highest tolerated dose (Gnerre et al.…”

Section: Introductionmentioning

confidence: 99%

“… 2018 ; Imai et al. 2019 ). Furthermore, the uridine 5′-diphosphoglucuronosyltransferase (UGT) enzymes, UGT1A3 and UGT2B7 are involved in the metabolism of ACT-333679 (Gnerre et al.…”

Section: Introductionmentioning

confidence: 99%

“…Some studies had indicated that ACT-333679 was approximately 3- to 4-fold higher than the parent drug at a steady-state after oral selexipag administration, while only about 1.3-fold higher than the parent drug after intravenous administration (Imai et al. 2019 ). It has been verified that ACT-333679 is the main contributor to the pharmacological effect due to 37-fold more potent than selexipag in activating the prostacyclin receptor (Kaufmann et al.…”

Section: Introductionmentioning

confidence: 99%

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Effect of quercetin on the pharmacokinetics of selexipag and its active metabolite in beagles

Luo

Chen

et al. 2021

Pharmaceutical Biology

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Context As an inhibitor cytochrome P450 family 2 subfamily C polypeptide 8 (CYP2C8), quercetin is a naturally occurring flavonoid with its glycosides consumed at least 100 mg per day in food. However, it is still unknown whether quercetin and selexipag interact. Objective The study investigated the effect of quercetin on the pharmacokinetics of selexipag and ACT-333679 in beagles. Materials and methods The ultra-performance liquid chromatography-tandem mass spectrometry ( UPLC-MS/MS) was used to investigate the pharmacokinetics of orally administered selexipag (2 mg/kg) with and without quercetin (2 mg/kg/day for 7 days) pre-treatment in beagles. The effect of quercetin on the pharmacokinetics of selexipag and its potential mechanism was studied through the pharmacokinetic parameters. Results The assay method was validated for selexipag and ACT-333679, and the lower limit of quantification for both was 1 ng/mL. The recovery and the matrix effect of selexipag were 84.5–91.58% and 94.98–99.67%, while for ACT-333679 were 81.21–93.90% and 93.17–99.23%. The UPLC-MS/MS method was sensitive, accurate and precise, and had been applied to the herb-drug interaction study of quercetin with selexipag and ACT-333679. Treatment with quercetin led to an increased in C max and AUC 0–t of selexipag by about 43.08% and 26.92%, respectively. While the ACT-333679 was about 11.11% and 18.87%, respectively. Discussion and conclusion The study indicated that quercetin could inhibit the metabolism of selexipag and ACT-333679 when co-administration. Therefore, the clinical dose of selexipag should be used with caution when co-administered with foods high in quercetin.

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Section: Introductionmentioning

confidence: 99%

“… 2018 ; Imai et al. 2019 ). Furthermore, the uridine 5′-diphosphoglucuronosyltransferase (UGT) enzymes, UGT1A3 and UGT2B7 are involved in the metabolism of ACT-333679 (Gnerre et al.…”

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Effect of quercetin on the pharmacokinetics of selexipag and its active metabolite in beagles

Luo

Chen

et al. 2021

Pharmaceutical Biology

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“…Selexipag is hydrolysed by carboxylesterases to its active metabolite, ACT‐333679 8,9 . The structures of both selexipag and ACT‐333679 have previously been published 8 .…”

Section: Introductionmentioning

confidence: 99%

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

Axelsen

Poggesi

Rasschaert

et al. 2020

Brit J Clinical Pharma

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Funding information Actelion Pharmaceuticals Aims: Selexipag is a prostacyclin receptor agonist approved for the treatment of pulmonary arterial hypertension. Cytochrome P450 (CYP) 2C8 is involved in the metabolism of selexipag and its active metabolite, ACT-333679. This study evaluated the interaction of selexipag and clopidogrel, a CYP2C8 inhibitor. Methods: The study had a 2-treatment, 1-sequence, crossover design. Pharmacokinetics (PK) and CYP2C8 genotype were assessed in healthy male subjects administered selexipag (200 μg twice daily [b.i.d.]) alone or with clopidogrel (300 mg single dose or 75 mg once daily [o.d.]). PK modelling and simulation were conducted to support dosing recommendations. Results: Clopidogrel had a comparatively small effect on selexipag (<1.5-fold difference in any PK variable). For ACT-333679, the major contributor to the drug effect, the area under the plasma concentration-time curve during a dose interval and the maximum plasma concentration increased 2.25-fold (90% confidence interval [CI] 2.06, 2.46) and 1.69-fold (90% CI 1.55, 1.84), respectively with clopidogrel 300 mg and 2.70-fold (90% CI 2.45, 2.96) and 1.90-fold (90% CI 1.72, 2.11), respectively with clopidogrel 75 mg. The effect of clopidogrel on selexipag and ACT-333679 exposure was comparable for all identified CYP2C8 genotypes. PK simulations predicted comparable exposure to ACT-333679 following selexipag 400 μg b.i.d., 400 μg o.d. in combination with clopidogrel 75 mg o.d and 200 μg b.i.d. with clopidogrel 75 mg o.d. Conclusion: Results suggest that ACT-333679 exposure can be maintained within the therapeutic range by reducing selexipag dosing frequency to o.d. or dose to half, when selexipag is coadministered with clopidogrel.

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“…[3][4][5][6][7] Selexipag is predominantly hydrolysed to its active metabolite ACT-333679 by liver carboxylesterase-1 (CES-1, 77.0%), and to a lesser extent by CES-2 (9.99%; Figure 1). 8 After oral administration, selexipag is rapidly absorbed and hydrolysed to its pharmacologically active metabolite, ACT-333679, and it is also metabolized into inactive metabolites by cytochrome P450 (CYP) 3A4. 3 The oral bioavailability of selexipag is 49.4%.…”

mentioning

confidence: 99%

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

Katayama

Odagiri

Hakamata

et al. 2020

Brit J Clinical Pharma

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The strong cytochrome P450 (CYP) 2C8 inhibitor gemfibrozil has been demonstrated to increase the area under the plasma concentration-time curve from 0 to infinity (AUC 0-∞) of ACT-333679, an active metabolite of selexipag, by 11-fold. Similarly to gemfibrozil, the CYP2C8 inhibitor clopidogrel increased ACT-333679 concentration by 1.9-fold after a single loading dose (300 mg once daily) and 2.7-fold after repeated treatment with the maintenance dose (75 mg once daily) in Europeans. However, the effects of clopidogrel on the pharmacokinetics of selexipag and ACT-333679 have not been fully elucidated in the Japanese population. Methods: We investigated the effect of clopidogrel on the pharmacokinetics of selexipag and ACT-333679 in 14 healthy Japanese volunteers. Results: The concomitant administration of clopidogrel with selexipag did not influence the maximum concentration and AUC 0-∞ of selexipag, whereas it significantly increased AUC 0-∞ of ACT-333679 by approximately 1.90-fold (90% confidence interval 1.69-2.14) without changing the maximum concentration. When selexipag was administered 1 day after clopidogrel was discontinued, the increase in AUC 0-∞ of ACT-333679 was 1.37-fold (90% confidence interval 0.93-2.02), suggesting that, although the inhibitory effect of clopidogrel on CYP2C8 was reduced, it persisted for at least 1 day after withdrawal. Conclusion: Our results demonstrated the impact of clopidogrel on the pharmacokinetics of selexipag and its active metabolite and suggested that selexipag should be carefully prescribed with clopidogrel with dose adjustment or reducing the dosing frequency in Japanese clinical settings.

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Contribution of Human Liver and Intestinal Carboxylesterases to the Hydrolysis of Selexipag In Vitro

Cited by 11 publications

References 28 publications

Effect of quercetin on the pharmacokinetics of selexipag and its active metabolite in beagles

Effect of quercetin on the pharmacokinetics of selexipag and its active metabolite in beagles

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

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

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