Functional autoantibodies against Endothelin-1 receptor type A and Angiotensin II receptor type 1 in patients with preeclampsia.

OBJECTIVES: Functional autoantibodies against Angiotensin II Receptor type 1 (AT1-AA) and Endothelin-1 Receptor type A (ETA-AA), which belong to the class of functional autoantibodies, have been discovered in patients with preeclampsia and in rodent models of pregnancy-induced hypertension. The aim of the study was to investigate the expression of these autoantibodies in relation to disease progression. STUDY DESIGN: We included 10 controls and 41 cases defined as patients with gestational-induced hypertension, preeclampsia or HELLP syndrome. MAIN OUTCOME: Serum obtained in the first trimester as well as at the time of disease development were analyzed by means of a biological assay of beating cardiomyocytes. We also measured the protein expression of IL-17A in these samples. RESULTS: 100% of samples from patients with gestational induced hypertension, preeclampsia or HELLP syndrome expressed AT1-AA when they presented with clinical symptoms but not in samples from the first trimester. 44% of samples from patients with severe preeclampsia or HELLP syndrome expressed ETA-AA but only when they presented with clinical symptoms. The controls expressed neither AT1-AA nor ETA-AA. Approximately 40% of patients with severe preeclampsia or HELLP syndrome expressed IL-17A, both at the time of the onset of symptoms and in the first trimester. CONCLUSION: Autoantibodies against the Angiotensin II receptor 1 and Endothelin receptor are developed in relation to pregnancy-induced hypertension and not present at the start of the pregnancy in these patients. IL-17A is increased in some patients with severe preeclampsia, but the expression is not related to the development of clinical symptoms.

Serious Liver Injury Associated with Macitentan: A Case Report.

Several endothelin receptor antagonists (ERAs) that were developed for the treatment of pulmonary arterial hypertension (PAH), including bosentan and sitaxentan, have been linked to clinically significant hepatocellular injury, as well as liver failure. We describe the first case of fulminant hepatitis to be reported in association with the ERA macitentan. This case was recently identified within the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS) and describes liver transplantation occurring 13 months after macitentan initiation in a young patient (23 years old) with idiopathic PAH New York Heart Association (NYHA) functional class III.

Pharmacokinetics of Macitentan in Patients With Pulmonary Arterial Hypertension and Comparison With Healthy Subjects.

Macitentan is a worldwide approved dual endothelin receptor antagonist that has demonstrated efficacy in the treatment of pulmonary arterial hypertension (PAH) in a phase 3 clinical trial, SERAPHIN, at a dose of 10 mg once daily. During this trial, trough plasma concentrations (Ctrough ) of macitentan and its active metabolite,  ACT-132577,  were obtained at steady state in 242 patients, indicating that mean Ctrough of both analytes was about 2-fold higher in PAH patients than in healthy subjects. To further investigate the pharmacokinetics (PK) of macitentan and its active metabolite, ACT-132577,  a 24-hour PK profile was recorded at steady state in 20 PAH patients in the open-label extension of SERAPHIN.  A cross-study comparison showed that although Ctrough in PAH patients is higher when compared with a historical reference group of healthy subjects, with geometric mean ratios of 1.45 and 1.36 for macitentan and ACT-132577, respectively, this does not translate to a significant difference in exposure expressed as maximum plasma concentration (Cmax ) or area under the plasma concentration-time curve over a dosing interval (AUCτ ). Geometric mean ratios for Cmax and AUCτ were 1.08 and 1.22, respectively, for macitentan and 1.24 and 1.31, respectively, for ACT-132577. Therefore, overall exposure at steady state to macitentan and ACT-132577 in PAH patients is considered similar to that in healthy subjects.

Lack of Pharmacokinetic Interactions Between Macitentan and a Combined Oral Contraceptive in Healthy Female Subjects.

Macitentan, a dual endothelin receptor antagonist used in pulmonary arterial hypertension, induces cytochrome P450 (CYP) 3A at supratherapeutic concentrations in vitro. Most combined oral hormonal contraceptives (OCs) are CYP3A substrates and their efficacy can be affected by CYP3A inducers. This randomized crossover study assessed possible pharmacokinetic (PK) interactions between macitentan and an OC containing ethinyl estradiol and norethindrone (or norethisterone). Twenty-six healthy women received a single oral dose of OC alone (reference) and concomitantly with 10 mg macitentan at steady state (test). No PK interaction was concluded if the 90% confidence intervals (CIs) of geometric mean ratios (GMRs; test/reference) of the peak plasma concentration (Cmax ) and the exposure from 0 to infinity (AUC0 - ∞ ) to the OC components were within the equivalence limits of 0.8 to 1.25. Cmax and AUC0-∞ of the OC were within the equivalence limits. For ethinyl estradiol, GMRs (90%CIs) of Cmax and AUC0-∞ were 0.92 (0.85-0.99) and 0.95 (0.90-0.99). For norethindrone, these values were 1.02 (0.95-1.09) and 1.04 (0.98-1.09), respectively. Overall, study treatments were well tolerated. No major changes from baseline in safety parameters were reported in either treatment. Macitentan does not affect the PK of OCs.