Effect of Macitentan on the Pharmacokinetics of the Breast Cancer Resistance Protein Substrates, Rosuvastatin and Riociguat, in Healthy Male Subjects

Abstract

BackgroundMacitentan is a clinically approved endothelin receptor antagonist for the treatment of pulmonary arterial hypertension (PAH). Increasing use of combination drug therapy in PAH means that it is important to recognize potential drug–drug interactions (DDIs) that could affect the efficacy and safety of macitentan in patients with PAH.ObjectiveTwo Phase 1 studies were conducted to investigate the effect of macitentan at steady-state on the pharmacokinetics of the breast cancer resistance protein (BCRP) substrates, rosuvastatin and riociguat in healthy male subjects. Another objective was to determine the safety and tolerability of concomitant administration of rosuvastatin or riociguat with macitentan.MethodsHealthy male subjects received a single oral dose of rosuvastatin 10 mg (n = 20) or riociguat 1 mg (n = 20) on Day 1 (reference treatment). A loading oral dose of macitentan 30 mg was administered on Day 5 followed by macitentan 10 mg once-daily from Day 6 to Day 15 (riociguat study) or Day 6 to Day 16 (rosuvastatin study). A concomitant oral dose of rosuvastatin 10 mg or riociguat 1 mg was administered on Day 10 (test treatment). Pharmacokinetics were evaluated for 96 h after treatment on Day 1 and for 144 h (riociguat study) or 168 h (rosuvastatin study) after treatment on Day 10. To compare the reference and test treatments, the geometric mean ratio was calculated for the maximum plasma concentration (Cmax), the area under the plasma concentration-time curve (AUC) from zero (pre-dose) to time of the last measured concentration above the limit of quantification (AUC0–t), the AUC from zero to infinity (AUC0–∞) and the terminal elimination half-life (t½) of rosuvastatin, riociguat and riociguat’s metabolite, M1. The difference in the time to reach maximum plasma concentration (tmax) was determined by the Wilcoxon test. Trough levels of macitentan and its metabolite, ACT-132577, were measured and safety was monitored throughout.ResultsNinety percent confidence intervals of the geometric mean ratios were within the bioequivalence criteria of 0.80–1.25. There was no significant difference between test and reference tmax. Rosuvastatin or riociguat did not affect the steady-state concentrations of macitentan and ACT-132577. The adverse event profile was consistent with the known safety profiles of the drugs.ConclusionsMacitentan 10 mg did not affect the pharmacokinetics of BCRP substrates, rosuvastatin or riociguat in healthy male subjects.EudraCT numbers: 2017–003095–31 and 2017–003502–41.

Aprocitentan: A new development of resistant hypertension

“…Moreover, aprocitentan exhibited 50% inhibition of the breast cancer resistance protein (BCRP) in vitro. Given that rosuvastatin is a substrate of organic anion‐transporting polypeptide and BCRP transporters, a single‐center, open‐label, single‐sequence, phase 1 study (NCT03245229) demonstrated that rosuvastatin did not influence plasma concentrations of aprocitentan 25,26 …”

Effects of Multiple‐Dose Administration of Aprocitentan on the Pharmacokinetics of Rosuvastatin

“…Rosuvastatin, a 3‐hydroxy‐3‐methyl‐glutaryl‐coenzyme A reductase inhibitor indicated for the treatment of hypercholesterolemia in the dose range of 5 to 40 mg is a substrate of various transporter proteins including BCRP and organic anion‐transporting polypeptides 11‐13 . Rosuvastatin was specifically selected, as it has also been used in the investigation of BCRP inhibition by another ERA, macitentan, of which aprocitentan was identified as a metabolite 14 . Additionally, rosuvastatin is a treatment of interest in the target population as patients with resistant hypertension have comorbid diseases such as chronic kidney disease, which often is associated with hypercholesterolemia 15 …”

“…[11][12][13] Rosuvastatin was specifically selected, as it has also been used in the investigation of BCRP inhibition by another ERA, macitentan, of which aprocitentan was identified as a metabolite. 14 Additionally, rosuvastatin is a treatment of interest in the target population as patients with resistant hypertension have comorbid diseases such as chronic kidney disease, which often is associated with hypercholesterolemia. 15…”