Pharmacokinetics of the Novel Dual Endothelin Receptor Antagonist Macitentan in Subjects With Hepatic or Renal Impairment

被引:29
|
作者
Sidharta, Patricia N. [1 ]
Lindegger, Nicolas [1 ]
Ulc, Ivan [2 ]
Dingemanse, Jasper [1 ]
机构
[1] Actel Pharmaceut Ltd, Dept Clin Pharmacol, CH-4123 Allschwil, Switzerland
[2] CEPHA Sro, Plzen, Czech Republic
来源
JOURNAL OF CLINICAL PHARMACOLOGY | 2014年 / 54卷 / 03期
关键词
pharmacokinetics; macitentan; endothelin receptor antagonist; renal function impairment; hepatic function impairment; SERUM CREATININE; HEALTHY-SUBJECTS; DYSFUNCTION; METABOLISM; BOSENTAN; HYPERTENSION; HUMANS; SAFETY;
D O I
10.1002/jcph.193
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
Macitentan is under development for the treatment of pulmonary arterial hypertension (PAH). Patients with PAH may suffer from comorbidities such as renal or hepatic impairment. Two prospective, single-center, open-label studies evaluated the pharmacokinetics of macitentan and its metabolites (pharmacologically active ACT-132577 and inactive ACT-373898) in healthy subjects and in subjects with mild, moderate, and severe hepatic impairment or severe renal function impairment (SRFI). After administering a single oral dose of 10mg macitentan the pharmacokinetic parameters including area under the curve from zero to infinity (AUC) were derived from plasma concentration-time profiles. Exposure to macitentan and ACT-132577 was lower in hepatically impaired versus healthy subjects, with no correlation with the degree of hepatic impairment. Exposure to ACT-373898 was lower in subjects with moderate hepatic impairment only. Plasma concentration-time profiles for macitentan and ACT-132577 (active) were similar in healthy subjects and subjects with SRFI. AUC of ACT-373898 (inactive) was 7.3-fold higher in subjects with SRFI versus healthy subjects. No safety concerns were raised in either study. Based on these observations, pharmacokinetic alterations of macitentan due to hepatic or renal function impairment are not considered clinically relevant and no dose adjustment is necessary in these patients.
引用
收藏
页码:291 / 300
页数:10
相关论文
共 50 条
  • [1] Investigation of the Effects of Ketoconazole on the Pharmacokinetics of Macitentan, a Novel Dual Endothelin Receptor Antagonist, in Healthy Subjects
    Atsmon, Jacob
    Dingemanse, Jasper
    Shaikevich, Dimitri
    Volokhov, Inna
    Sidharta, Patricia N.
    [J]. CLINICAL PHARMACOKINETICS, 2013, 52 (08) : 685 - 692
  • [2] Investigation of the Effects of Ketoconazole on the Pharmacokinetics of Macitentan, a Novel Dual Endothelin Receptor Antagonist, in Healthy Subjects
    Jacob Atsmon
    Jasper Dingemanse
    Dimitri Shaikevich
    Inna Volokhov
    Patricia N. Sidharta
    [J]. Clinical Pharmacokinetics, 2013, 52 : 685 - 692
  • [3] PHARMACOKINETICS, TOLERABILITY, AND SAFETY OF THE DUAL ENDOTHELIN RECEPTOR ANTAGONIST MACITENTAN IN JAPANESE AND CAUCASIAN HEALTHY SUBJECTS
    Bruderer, S.
    Marjason, J.
    Sidharta, P.
    Dingemanse, J.
    [J]. CLINICAL PHARMACOLOGY & THERAPEUTICS, 2011, 89 : S83 - S83
  • [4] Clinical Pharmacokinetics and Pharmacodynamics of the Endothelin Receptor Antagonist Macitentan
    Sidharta, P. N.
    Treiber, A.
    Dingemanse, J.
    [J]. CLINICAL PHARMACOKINETICS, 2015, 54 (05) : 457 - 471
  • [5] Single-dose pharmacokinetics, safety, and tolerability of the dual endothelin receptor antagonist aprocitentan in subjects with moderate hepatic impairment
    Fontes, Magda S. C.
    Dingemanse, Jasper
    Halabi, Atef
    Tomaszewska-Kiecana, Monika
    Sidharta, Patricia N.
    [J]. SCIENTIFIC REPORTS, 2022, 12 (01)
  • [6] Single-dose pharmacokinetics, safety, and tolerability of the dual endothelin receptor antagonist aprocitentan in subjects with moderate hepatic impairment
    Magda S. C. Fontes
    Jasper Dingemanse
    Atef Halabi
    Monika Tomaszewska-Kiecana
    Patricia N. Sidharta
    [J]. Scientific Reports, 12
  • [7] Clinical Pharmacokinetics and Pharmacodynamics of the Endothelin Receptor Antagonist Macitentan
    P. N. Sidharta
    A. Treiber
    J. Dingemanse
    [J]. Clinical Pharmacokinetics, 2015, 54 : 457 - 471
  • [8] Single-dose pharmacokinetics and tolerability of aprocitentan, a dual endothelin receptor antagonist, in subjects with severe renal function impairment
    Sidharta, P. N.
    Ulc, I.
    Dingemanse, J.
    [J]. EUROPEAN JOURNAL OF CLINICAL PHARMACOLOGY, 2019, 75 : S92 - S92
  • [9] Single-Dose Pharmacokinetics and Tolerability of Aprocitentan, a Dual Endothelin Receptor Antagonist, in Subjects with Severe Renal Function Impairment
    Patricia N. Sidharta
    Ivan Ulč
    Jasper Dingemanse
    [J]. Clinical Drug Investigation, 2019, 39 : 1117 - 1123
  • [10] Single-Dose Pharmacokinetics and Tolerability of Aprocitentan, a Dual Endothelin Receptor Antagonist, in Subjects with Severe Renal Function Impairment
    Sidharta, Patricia N.
    Ulc, Ivan
    Dingemanse, Jasper
    [J]. CLINICAL DRUG INVESTIGATION, 2019, 39 (11) : 1117 - 1123