PMID- 31552642
OWN - NLM
STAT- MEDLINE
DCOM- 20200127
LR  - 20200127
IS  - 1179-1918 (Electronic)
IS  - 1173-2563 (Print)
IS  - 1173-2563 (Linking)
VI  - 39
IP  - 12
DP  - 2019 Dec
TI  - Effect of Macitentan on the Pharmacokinetics of the Breast Cancer Resistance 
      Protein Substrates, Rosuvastatin and Riociguat, in Healthy Male Subjects.
PG  - 1223-1232
LID - 10.1007/s40261-019-00857-7 [doi]
AB  - BACKGROUND: Macitentan 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. OBJECTIVE: Two 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. METHODS: Healthy 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 (C(max)), 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 (AUC(0-t)), the AUC from 
      zero to infinity (AUC(0-infinity)) and the terminal elimination half-life (t((1/2))) of 
      rosuvastatin, riociguat and riociguat's metabolite, M1. The difference in the 
      time to reach maximum plasma concentration (t(max)) was determined by the 
      Wilcoxon test. Trough levels of macitentan and its metabolite, ACT-132577, were 
      measured and safety was monitored throughout. RESULTS: Ninety 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 t(max). 
      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. CONCLUSIONS: Macitentan 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.
FAU - Csonka, Denes
AU  - Csonka D
AUID- ORCID: 0000-0001-7797-2615
AD  - Actelion Pharmaceuticals Ltd, Gewerbestrasse 16, 4123, Allschwil, Switzerland. 
      dcsonka@its.jnj.com.
FAU - Bruderer, Shirin
AU  - Bruderer S
AD  - Actelion Pharmaceuticals Ltd, Gewerbestrasse 16, 4123, Allschwil, Switzerland.
FAU - Schultz, Armin
AU  - Schultz A
AD  - Clinical Research Services Mannheim GmbH, Mannheim, Germany.
FAU - Soergel, Marianne
AU  - Soergel M
AD  - Actelion Pharmaceuticals Ltd, Gewerbestrasse 16, 4123, Allschwil, Switzerland.
FAU - Stepanova, Radka
AU  - Stepanova R
AD  - Aixial s.r.o., Brno, Czech Republic.
FAU - Sabattini, Giancarlo
AU  - Sabattini G
AD  - Idorsia Pharmaceuticals Ltd., Allschwil, Switzerland.
FAU - Perez-Ruixo, Juan Jose
AU  - Perez-Ruixo JJ
AD  - Janssen Global Clinical Pharmacology, Turnhoutseweg, Beerse, Belgium.
LA  - eng
PT  - Journal Article
PL  - New Zealand
TA  - Clin Drug Investig
JT  - Clinical drug investigation
JID - 9504817
RN  - 0 (ABCG2 protein, human)
RN  - 0 (ATP Binding Cassette Transporter, Subfamily G, Member 2)
RN  - 0 (Neoplasm Proteins)
RN  - 0 (Pyrazoles)
RN  - 0 (Pyrimidines)
RN  - 0 (Sulfonamides)
RN  - 83MVU38M7Q (Rosuvastatin Calcium)
RN  - RU3FE2Y4XI (riociguat)
RN  - Z9K9Y9WMVL (macitentan)
SB  - IM
MH  - ATP Binding Cassette Transporter, Subfamily G, Member 2/*metabolism
MH  - Adolescent
MH  - Adult
MH  - Drug Interactions
MH  - Healthy Volunteers
MH  - Humans
MH  - Male
MH  - Middle Aged
MH  - Neoplasm Proteins/*metabolism
MH  - Pyrazoles/*pharmacokinetics
MH  - Pyrimidines/*pharmacokinetics/*pharmacology
MH  - Rosuvastatin Calcium/*pharmacokinetics
MH  - Sulfonamides/*pharmacology
MH  - Young Adult
PMC - PMC6842351
COIS- Denes Csonka, Shirin Bruderer, Marianne Soergel and Juan Jose Perez Ruixo are 
      employees of Actelion Pharmaceuticals Ltd. Armin Schultz is an employee of the 
      clinical research organization Clinical Research Services Mannheim GmbH, which 
      carried out the studies reported. Radka Stepanova is an employee of the clinical 
      research organization Aixial s.r.o, which performed the biostatistics for the 
      studies reported. Giancarlo Sabattini is an employee of Idorsia Pharmaceuticals 
      Ltd, which collaborated on the studies reported.
EDAT- 2019/09/26 06:00
MHDA- 2020/01/28 06:00
PMCR- 2019/09/24
CRDT- 2019/09/26 06:00
PHST- 2019/09/26 06:00 [pubmed]
PHST- 2020/01/28 06:00 [medline]
PHST- 2019/09/26 06:00 [entrez]
PHST- 2019/09/24 00:00 [pmc-release]
AID - 10.1007/s40261-019-00857-7 [pii]
AID - 857 [pii]
AID - 10.1007/s40261-019-00857-7 [doi]
PST - ppublish
SO  - Clin Drug Investig. 2019 Dec;39(12):1223-1232. doi: 10.1007/s40261-019-00857-7.