title: Interaction of ambrisentan with clarithromycin and its modulation by polymorphic SLCO1B1.
abstract: OBJECTIVE
  We assessed the effect of cytochrome P450 (CYP) 3A4 and the OATP1B1 inhibitor clarithromycin on ambrisentan steady-state kinetics and its relationship to the SLCO1B1 15 haplotype in healthy volunteers.
  
  
  METHODS
  In this open-label, monocenter, one-sequence crossover clinical trial ten male healthy participants were stratified according to CYP2C19 and SLCO1B1 (encoding for OATP1B1) genotype into two groups: group 1 (n = 6), with CYP2C19 1/1 (extensive metabolizer, EM) and SLCO1B1 wild-type; group 2 (n = 4), with CYP2C19 EM and homozygous (n = 3) or heterozygous for SLCO1B1 15 (n = 1). The participants were administered a once-daily oral dose of 5 mg ambrisentan on study days 1 and days 3-14 and twice-daily oral doses of 500 mg clarithromycin on study days 11-14. To monitor CYP3A activity 3 mg midazolam was given orally 1 day before the first ambrisentan administration and on days 1, 10, and 14 of ambrisentan treatment. Ambrisentan plasma kinetics was assessed on days 1 (single dose), 10 (steady-state), and 14 (CYP3A4/OATP1B1 inhibition by clarithromycin).
  
  
  RESULTS
  Consistent with the expectation that ambrisentan does not induce its own metabolism, ambrisentan exposure and peak concentration (Cmax) were similar after the first dose and at steady-state. Clarithromycin increased the area under the plasma concentration-time curve of ambrisentan by 41 % and Cmax by 27 % (n = 10, both p < 0.05). No contribution of SLCO1B1*15 to the extent of this interaction was observed.
  
  
  CONCLUSIONS
  Clarithromycin increased ambrisentan exposure to a similar extent to ketoconazole, namely, clinically minor and likely irrelevant.
authors.affiliation: Department of Clinical Pharmacology and Pharmacoepidemiology, University Hospital of Heidelberg, University of Heidelberg, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Markert
authors.forename: Regina
authors.initials: R
authors.lastname: Hellwig
authors.forename: Jürgen
authors.initials: J
authors.lastname: Burhenne
authors.forename: Michael Marcus
authors.initials: MM
authors.lastname: Hoffmann
authors.forename: Johanna
authors.initials: J
authors.lastname: Weiss
authors.forename: Gerd
authors.initials: G
authors.lastname: Mikus
authors.forename: Walter E
authors.initials: WE
authors.lastname: Haefeli
mesh_terms: D000284:Administration, Oral; D000328:Adult; D019540:Area Under Curve; D017291:Clarithromycin / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D018592:Cross-Over Studies; D051544:Cytochrome P-450 CYP3A / Q000235:genetics*; D065692:Cytochrome P-450 CYP3A Inhibitors; D004334:Drug Administration Schedule; D004347:Drug Interactions; D005260:Female; D005787:Gene Frequency; D006801:Humans; D027381:Liver-Specific Organic Anion Transporter 1; D008297:Male; D008657:Metabolic Clearance Rate; D008874:Midazolam / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology; D033281:Nontherapeutic Human Experimentation; D027361:Organic Anion Transporters / Q000037:antagonists & inhibitors / Q000235:genetics*; D010666:Phenylpropionates / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D011110:Polymorphism, Genetic; D011724:Pyridazines / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology
chemical_list: D065692:Cytochrome P-450 CYP3A Inhibitors; D027381:Liver-Specific Organic Anion Transporter 1; D027361:Organic Anion Transporters; D010666:Phenylpropionates; D011724:Pyridazines; C503999:SLCO1B1 protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D017291:Clarithromycin; C467894:ambrisentan; D008874:Midazolam