PMID- 32035014
OWN - NLM
STAT- MEDLINE
DCOM- 20210625
LR  - 20210625
IS  - 1552-4604 (Electronic)
IS  - 0091-2700 (Linking)
VI  - 60
IP  - 7
DP  - 2020 Jul
TI  - Impact of the Selective Orexin-1 Receptor Antagonist ACT-539313 on the 
      Pharmacokinetics of the CYP3A Probe Drug Midazolam in Healthy Male Subjects.
PG  - 931-941
LID - 10.1002/jcph.1588 [doi]
AB  - ACT-539313 is a potent and selective orexin-1 receptor antagonist. CYP3A is the 
      major cytochrome P450 (CYP) enzyme involved in the metabolism and clearance of 
      ACT-539313 in man. The main objective of this study was to investigate the effect 
      of ACT-539313 on the pharmacokinetics of orally administered midazolam. Thereby, 
      this single-center, open-label, fixed-sequence study investigated the CYP3A 
      interaction potential of ACT-539313 following single- (on day 2) and 
      repeated-dose (on day 11) twice-daily administration of 200 mg ACT-539313. 
      Exposure to midazolam was higher during concomitant administration of single as 
      well as after repeated doses of ACT-539313 over 10 days compared to midazolam 
      alone (day 1). In the presence of ACT-539313, the geometric mean ratio of the 
      maximum plasma concentration and the area under the plasma concentration-time 
      curve from time 0 to 24 hours increased by 1.18- and 1.79-fold on day 2, and by 
      2.13- and 4.54-fold on day 11, respectively. A similar outcome was also shown in 
      the additionally evaluated urinary 6beta-hydroxycortisol/cortisol ratio (6beta-CR), as 
      the geometric mean ratio of the 6beta-CR showed a decrease to 0.78 on day 2 and to 
      0.61 on day 11. The most commonly reported adverse events (AEs) included 
      somnolence and headache. All AEs were transient and of mild intensity. No 
      treatment-related effects on vital signs, clinical laboratory, and 
      electrocardiogram were observed. In summary, the observed corresponding decrease 
      of both the validated, exogenous (midazolam/1-hydroxymidazolam ratio) and a 
      frequently used endogenous (6beta-CR) marker of CYP3A activity is indicative of 
      CYP3A inhibition occurring after ACT-539313 treatment.
CI  - (c) 2020, The American College of Clinical Pharmacology.
FAU - Berger, Benjamin
AU  - Berger B
AUID- ORCID: 0000-0001-7777-5734
AD  - Department of Clinical Pharmacology, Idorsia Pharmaceuticals Ltd, Allschwil, 
      Switzerland.
FAU - Kaufmann, Priska
AU  - Kaufmann P
AUID- ORCID: 0000-0003-2415-3012
AD  - Department of Clinical Pharmacology, Idorsia Pharmaceuticals Ltd, Allschwil, 
      Switzerland.
FAU - Koch, Annelize
AU  - Koch A
AD  - Simbec Research Ltd, Merthyr Tydfil, United Kingdom.
FAU - Dingemanse, Jasper
AU  - Dingemanse J
AUID- ORCID: 0000-0002-4083-5817
AD  - Department of Clinical Pharmacology, Idorsia Pharmaceuticals Ltd, Allschwil, 
      Switzerland.
LA  - eng
PT  - Clinical Trial, Phase I
PT  - Journal Article
DEP - 20200208
PL  - England
TA  - J Clin Pharmacol
JT  - Journal of clinical pharmacology
JID - 0366372
RN  - 0 (Biomarkers)
RN  - 0 (Cytochrome P-450 CYP3A Inhibitors)
RN  - 0 (Orexin Receptor Antagonists)
RN  - 0 (Orexin Receptors)
RN  - 53-35-0 (6 beta-hydroxycortisol)
RN  - E5142BN92Z (1-hydroxymethylmidazolam)
RN  - EC 1.14.14.1 (CYP3A protein, human)
RN  - EC 1.14.14.1 (Cytochrome P-450 CYP3A)
RN  - R60L0SM5BC (Midazolam)
RN  - WI4X0X7BPJ (Hydrocortisone)
SB  - IM
MH  - Adult
MH  - Area Under Curve
MH  - Biomarkers/blood
MH  - Cytochrome P-450 CYP3A/drug effects/*metabolism
MH  - Cytochrome P-450 CYP3A Inhibitors/administration & dosage/adverse 
      effects/blood/*pharmacokinetics
MH  - Drug Administration Schedule
MH  - Drug Interactions
MH  - Healthy Volunteers
MH  - Humans
MH  - Hydrocortisone/analogs & derivatives/urine
MH  - Male
MH  - Midazolam/administration & dosage/adverse effects/analogs & 
      derivatives/blood/*pharmacokinetics
MH  - Middle Aged
MH  - Orexin Receptor Antagonists/administration & dosage/adverse 
      effects/blood/*pharmacokinetics
MH  - Orexin Receptors/drug effects/*metabolism
MH  - Young Adult
OTO - NOTNLM
OT  - CYP3A
OT  - cytochrome P450
OT  - drug-drug interaction
OT  - metabolism
OT  - pharmacokinetics
OT  - selective orexin-1 receptor antagonist
EDAT- 2020/02/09 06:00
MHDA- 2021/06/29 06:00
CRDT- 2020/02/09 06:00
PHST- 2019/12/19 00:00 [received]
PHST- 2020/01/17 00:00 [accepted]
PHST- 2020/02/09 06:00 [pubmed]
PHST- 2021/06/29 06:00 [medline]
PHST- 2020/02/09 06:00 [entrez]
AID - 10.1002/jcph.1588 [doi]
PST - ppublish
SO  - J Clin Pharmacol. 2020 Jul;60(7):931-941. doi: 10.1002/jcph.1588. Epub 2020 Feb 
      8.