title: Influence of chronic hepatitis C infection on cytochrome P450 3A4 activity using midazolam as an in vivo probe substrate.
abstract: OBJECTIVE
  Inflammation-related changes in pharmacokinetics have been described for a number of disease-states including cancer, infection, and autoimmune disorders. This study examined the impact of chronic hepatitis C infection (CHC) on the pharmacokinetics of the cytochrome P450 3A probe midazolam in patients without significant liver disease who were either treatment naïve or prior interferon null-responders.
  
  
  METHODS
  Data were pooled from three studies which compared the pharmacokinetics of oral midazolam in healthy volunteers (n = 107) and in treatment-naive patients (n = 35) and interferon-null responders (n = 24) with CHC but without significant liver disease. Oral midazolam was administered as a single 2 mg oral dose, followed by frequent pharmacokinetic sampling and determination of the pharmacokinetics of midazolam and its α-hydroxy metabolite. CYP3A activity was determined by the metabolic ratio (MR) of the AUC metabolite/AUC parent and compared across groups as the mean effect ratio (test/reference).
  
  
  RESULTS
  The midazolam MR was lower in treatment-naïve patients with CHC than in health volunteers with a mean effect ratio of 0.63 [90 % confidence interval (CI) 0.56-0.72]. The effect was more pronounced in null-responders, who demonstrated a mean MR effect ratio of 0.46 (90 % CI 0.39-0.53) compared to volunteers. The mean area under the concentration-time curve (AUCinf) for midazolam in healthy volunteers, naïve patients, and null-responders was 32.3 [coefficient of variation (CV%) 41], 36.5 (CV% 33.5), and 55.3 (CV% 36.9) ng.h/mL, respectively.
  
  
  CONCLUSIONS
  The results of this study demonstrate a reduction in CYP3A4 activity between healthy volunteers and patients with CHC, with interferon null-responders demonstrating the most substantial difference. These results may have implications for the pharmacotherapy of patients infected with CHC.
authors.affiliation: Department of Clinical Pharmacology, Pharma Research and Early Development, Roche, Inc., Nutley, NJ, USA.
authors.forename: P N
authors.initials: PN
authors.lastname: Morcos
authors.forename: S A
authors.initials: SA
authors.lastname: Moreira
authors.forename: B J
authors.initials: BJ
authors.lastname: Brennan
authors.forename: S
authors.initials: S
authors.lastname: Blotner
authors.forename: N S
authors.initials: NS
authors.lastname: Shulman
authors.forename: P F
authors.initials: PF
authors.lastname: Smith
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D019540:Area Under Curve; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism*; D005260:Female; D016174:Hepacivirus / Q000235:genetics; D019698:Hepatitis C, Chronic / Q000201:enzymology* / Q000821:virology; D006801:Humans; D016018:Least-Squares Analysis; D008297:Male; D008657:Metabolic Clearance Rate; D008874:Midazolam / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D008875:Middle Aged; D055815:Young Adult
chemical_list: C040081:1-hydroxymethylmidazolam; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D008874:Midazolam