Effects of Multiple-Dose Administration of Aprocitentan on the Pharmacokinetics of Rosuvastatin.

Abstract

Aprocitentan is an investigational, orally active, dual, endothelin receptor antagonist that targets a novel pathway in the treatment of difficult-to-control (resistant) hypertension. The drug-drug interaction potential of aprocitentan on the breast cancer resistance protein (BCRP) transporter substrate rosuvastatin was investigated in this single-center, open-label, single-sequence study. Twenty healthy male subjects received a single dose of 10-mg rosuvastatin on days 1 and 13 followed by pharmacokinetic and tolerability assessments for up to 120 hours. From day 5 to day 17, subjects received 25 mg of aprocitentan once daily. Seventeen of 20 enrolled subjects completed the treatment. At steady state, aprocitentan did not affect the pharmacokinetics of rosuvastatin in a clinically relevant way. The maximum plasma concentration was increased by 40% with a 90% confidence interval of 1.19 to 1.65. However, the ratio of the geometric means for both area under the plasma concentration-time curve from time 0 to time t and area under the plasma concentration-time curve from time 0 to infinity was close to 1 with the 90% confidence interval within a reference interval of 0.80 to 1.25. Adverse events leading to study discontinuation were reported in 2 subjects. Overall, the combination of rosuvastatin and aprocitentan was well tolerated. Based on these data, aprocitentan does not affect BCRP and can be administered concomitantly with drugs dependent on BCRP transport.

• Authors: Patricia N Sidharta, Jasper Dingemanse
• Journal: Clinical pharmacology in drug development (Clin Pharmacol Drug Dev) Vol. 9 Issue 8 Pg. 995-1002 (11 2020) ISSN: 2160-7648 [Electronic] United States
• PMID: 32592633 (Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2020, The American College of Clinical Pharmacology.

Chemical References

• ABCG2 protein, human
• ATP Binding Cassette Transporter, Subfamily G, Member 2
• Anticholesteremic Agents
• Endothelin Receptor Antagonists
• Neoplasm Proteins
• Pyrimidines
• Sulfonamides
• Rosuvastatin Calcium
• aprocitentan

Topics

• ATP Binding Cassette Transporter, Subfamily G, Member 2 (drug effects)
• Administration, Oral
• Adult
• Anticholesteremic Agents (administration & dosage, blood, pharmacokinetics)
• Area Under Curve
• Dose-Response Relationship, Drug
• Drug Administration Schedule
• Drug Interactions (physiology)
• Drug Therapy, Combination (adverse effects, statistics & numerical data)
• Drug Tolerance
• Endothelin Receptor Antagonists (administration & dosage, adverse effects, therapeutic use)
• Healthy Volunteers (statistics & numerical data)
• Humans
• Hypertension (drug therapy)
• Male
• Middle Aged
• Neoplasm Proteins (drug effects)
• Pyrimidines (administration & dosage, adverse effects, therapeutic use)
• Rosuvastatin Calcium (administration & dosage, blood, pharmacokinetics)
• Sulfonamides (administration & dosage, adverse effects, therapeutic use)