title: Effect of  posaconazole  on the pharmacokinetics of simvastatin and midazolam in healthy volunteers.
abstract: OBJECTIVE
  The aim of the study is to determine the effect of posaconazole , an extended-spectrum triazole, on the pharmacokinetics of the HMG-CoA reductase inhibitor, simvastatin.
  
  
  METHODS
  This randomized, fixed-sequence, parallel-group, single-center, open-label study was conducted in 35 healthy volunteers randomly assigned to receive one of three doses of oral posaconazole: 50, 100 or 200 mg. All subjects received single doses of the reference drug midazolam (2 mg oral) alone on day -9; simvastatin (40 mg oral) alone on day -6; posaconazole (50, 100 or 200 mg) on days 1 - 7 once daily (q.d.); posaconazole plus midazolam (day 8); posaconazole alone (days 9 - 10); posaconazole plus simvastatin (day 11) and posaconazole alone (days 12 - 13).
  
  
  RESULTS
  Relative to simvastatin alone, posaconazole (50, 100 and 200 mg q.d.) significantly increased the C(max) and AUC of simvastatin (5- to 11-fold increase in AUC) and simvastatin acid (5- to 8-fold increase in AUC) during co-administration. Relative to midazolam alone, posaconazole (50, 100 and 200 mg q.d.) significantly inhibited CYP3A4-mediated metabolism of midazolam (three to sixfold increase in AUC).
  
  
  CONCLUSIONS
  These findings support the classification of posaconazole as a strong CYP3A4 inhibitor. Simvastatin, or other statins predominantly metabolized by CYP3A4, should not be co-administered with posaconazole. Other statins, whose metabolism/elimination is not affected by CYP3A4 inhibition, should be considered for co-administration.
authors.affiliation: Merck Sharp & Dohme Corp., Whitehouse Station, K15-2-2650, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA. gkrishna@optonline.net
authors.forename: Gopal
authors.initials: G
authors.lastname: Krishna
authors.forename: Lei
authors.initials: L
authors.lastname: Ma
authors.forename: Pratapa
authors.initials: P
authors.lastname: Prasad
authors.forename: Allen
authors.initials: A
authors.lastname: Moton
authors.forename: Monika
authors.initials: M
authors.lastname: Martinho
authors.forename: Edward
authors.initials: E
authors.lastname: O'Mara
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism*; D065692:Cytochrome P-450 CYP3A Inhibitors; D004347:Drug Interactions / Q000502:physiology; D005260:Female; D006801:Humans; D008297:Male; D008874:Midazolam / Q000008:administration & dosage / Q000097:blood*; D008875:Middle Aged; D019821:Simvastatin / Q000008:administration & dosage / Q000097:blood*; D014230:Triazoles / Q000008:administration & dosage / Q000097:blood*; D055815:Young Adult
chemical_list: D065692:Cytochrome P-450 CYP3A Inhibitors; D014230:Triazoles; C101425:posaconazole; D019821:Simvastatin; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D008874:Midazolam