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. 2021 Jan;87(1):119-128.
doi: 10.1111/bcp.14365. Epub 2020 Jun 5.

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

Lene Nygaard Axelsen  1 , Italo Poggesi  1 , Freya Rasschaert  2 , Juan Jose Perez Ruixo  1 , Shirin Bruderer  1
Affiliations

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

Lene Nygaard Axelsen et al. Br J Clin Pharmacol. 2021 Jan.

Abstract

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.

Trial registration: ClinicalTrials.gov NCT03496506.

Keywords: CYP2C8; clopidogrel; drug interactions; pharmacokinetics; selexipag.

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Conflict of interest statement

All authors are employees of Actelion Pharmaceuticals Ltd. or Janssen Pharmaceutica NV and may own company stocks.

Figures

FIGURE 1
FIGURE 1
Study design. During treatment A, subjects received selexipag 200 μg b.i.d. administered in the morning and evening of Days 1–3. During treatment B1, subjects received a single loading dose of clopidogrel 300 mg and selexipag 200 μg in the morning of Day 4 and selexipag 200 μg in the evening of Day 4. During treatment B2, subjects received a maintenance dose of clopidogrel 75 mg and selexipag 200 μg in the morning of Days 5–10 and selexipag 200 μg in the evening of Days 5–9. b.i.d. = twice daily; EOS = end of study; o.d. = once daily
FIGURE 2
FIGURE 2
Arithmetic mean (+ standard deviation) plasma concentration–time profile of selexipag and ACT‐333679 after administration with selexipag 200 μg b.i.d. (treatment A, n = 21), a single loading dose of clopidogrel 300 mg and selexipag 200 μg b.i.d. (treatment B1, n = 21) and clopidogrel 75 mg o.d. and selexipag 200 μg b.i.d. (treatment B2, n = 20). Data are presented on both linear (upper graphs) and semilogarithmic (lower graphs) scales. b.i.d. = twice daily; o.d. = once daily; SD = standard deviation
FIGURE 3
FIGURE 3
Individual and mean ± standard deviation of area under the plasma concentration–time curve during a dose interval at steady state (AUCτ,ss) of selexipag and ACT‐333679 after administration with selexipag 200 μg b.i.d. (treatment A, n = 21), and clopidogrel 75 mg o.d. and selexipag 200 μg b.i.d. (treatment B2, n = 20) presented by CYP2C8 genotype (*1/*1 n = 13, *1/*3 n = 6, *1/*4 n = 2). The AUCτ,ss ratio between treatment B2 (clopidogrel 75 mg o.d. and selexipag 200 μg b.i.d.) and treatment a (selexipag 200 μg b.i.d.), as well as geometric mean ratio with 95% confidence interval per CYP2C8 genotype (*1/*1 n = 12, *1/*3 n = 6, *1/*4 n = 2). Individual values are included as black circles. b.i.d. = twice daily; o.d. = once daily
FIGURE 4
FIGURE 4
The steady‐state pharmacokinetic profiles of ACT‐333679 following simulated dosing. (A) Selexipag 400 μg o.d. with clopidogrel 75 mg o.d. (regimen B, dashed red lines) and selexipag 400 μg b.i.d. (regimen A (reference dose), solid blue lines). (B) Selexipag 200 μg b.i.d. with clopidogrel 75 mg o.d. (regimen C, dashed red lines) and selexipag 400 μg b.i.d. (regimen A [reference dose], solid blue lines). Thick and thin lines represent the median and 5th–95th percentiles of 500 model‐based predictions, respectively. b.i.d. = twice daily; o.d. = once daily
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