To evaluate the impact of CYP2C19 polymorphisms on ambrisentan exposure and to assess its modification by St. John's wort (SJW), 20 healthy volunteers (10 CYP2C19 extensive, four poor and six ultrarapid metabolizers) received therapeutic doses of ambrisentan (5 mg qd po) for 20 days and concomitantly SJW (300 mg tid po) for the last 10 days. To quantify changes of CYP3A4 activity, midazolam (3 mg po) as a probe drug was used. Ambrisentan pharmacokinetics was assessed on days 1, 10 and 20, and midazolam pharmacokinetics before and on days 1, 10, 17 and 20. At steady state, ambrisentan exposure was similar in extensive and ultrarapid metabolizers but 43% larger in poor metabolizers (p < 0.01). In all volunteers, SJW reduced ambrisentan exposure and the relative change (17-26%) was similar in all genotype groups. The extent of this interaction did not correlate with the changes in CYP3A activity (midazolam clearance) (rs = 0.23, p = 0.34). Ambrisentan had no effect on midazolam pharmacokinetics. In conclusion, SJW significantly reduced exposure with ambrisentan irrespective of the CYP2C19 genotype. The extent of this interaction was small and thus likely without clinical relevance.
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http://dx.doi.org/10.1111/bcpt.12332 | DOI Listing |
JAMA Netw Open
July 2024
Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
Importance: Endothelin receptor antagonists are first-line therapy for pulmonary arterial hypertension (PAH). The first 2 agents approved in the class, bosentan and ambrisentan, initially carried boxed warnings for hepatotoxicity and required monthly liver function tests (LFTs) as part of a risk evaluation and mitigation strategy (REMS); however, in 2011, as further safety data emerged on ambrisentan, the boxed hepatotoxicity warning and LFT requirements were removed.
Objective: To analyze changes in the use of and LFT monitoring for ambrisentan and bosentan after changes to the ambrisentan labeling and REMS.
Eur J Pediatr
May 2024
Center for Congenital Heart Diseases, Pediatric Cardiology, Beatrix Children's Hospital, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
This open-label, extension study assessed long-term safety, tolerability, and efficacy of ambrisentan in a pediatric population (age 8- < 18 years) with pulmonary arterial hypertension (PAH). Following completion of a 6-month, randomized study, participants entered the long-term extension at individualized ambrisentan dosages (2.5/5/7.
View Article and Find Full Text PDFJ Clin Pharmacol
May 2023
Clinical Pharmacology Modeling and Simulation, GSK, Stevenage, Hertfordshire, UK.
This study aimed to develop a population pharmacokinetic (PK) model of ambrisentan in pediatric patients (8 to <18 years) with pulmonary arterial hypertension (PAH) and compare pediatric ambrisentan systemic exposure with previously reported adult data. Association of ambrisentan exposure with efficacy (6-minute walking distance) and safety (adverse events) were exploratory analyses. A population PK model was developed using pediatric PK data.
View Article and Find Full Text PDFPediatr Crit Care Med
September 2020
Division of Pediatric Cardiology, Department of Pediatrics, Duke University Pediatric and Congenital Heart Center, Durham, NC.
Objectives: To determine the pharmacokinetics, pharmacodynamics, and safety of the hepatically metabolized endothelin receptor antagonist, ambrisentan in children after Fontan surgery.
Design: Prospective, randomized, double-blind, placebo-controlled pharmacokinetic/pharmacodynamics and safety trial.
Setting: Single-center, postoperative cardiac ICU.
BMC Nephrol
January 2020
Fundacio Lluita contra la SIDA, Barcelona, Spain.
Background: Ambrisentan is a selective endothelin receptor antagonist used for the treatment of pulmonary arterial hypertension (PAH). Little is known about ambrisentan removal by hemodialysis in patients with end-stage renal disease (ESRD).
Case Presentation: A 53-year-old woman with HIV/hepatitis C virus (HCV) co-infection, PAH and ESRD on regular hemodialyis was admitted in our hospital due to refractory heart failure while on treatment with bosentan (125 mg twice daily) and tadalafil (20 mg once daily) for PAH and antiretroviral treatment (cART) including darunavir/cobicistat (800/150 mg once daily).
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