title: Effect of low-dose ritonavir (100 mg twice daily) on the activity of cytochrome P450 2D6 in healthy volunteers.
abstract: OBJECTIVE
  In the treatment of human immunodeficiency virus infection, the protease inhibitor ritonavir is used in a low dose (100 mg twice daily) to inhibit cytochrome P450 (CYP) 3A4 and thereby increase plasma concentrations of coadministered protease inhibitors. When applied in a therapeutic dose (600 mg twice daily), ritonavir also inhibits CYP2D6. The effect of low-dose ritonavir on CYP2D6 is unknown and was investigated in this study.
  
  
  METHODS
  This was a 1-arm, 2-period, fixed-order study in 13 healthy male volunteers who were extensive metabolizers of CYP2D6. The first period examined baseline CYP2D6 activity by evaluating the pharmacokinetics of a single dose of desipramine and by metabolic phenotyping with dextromethorphan. During the second period, participants took ritonavir, 100 mg twice daily, for 2 weeks, followed by repeat assessment of desipramine pharmacokinetics and the dextromethorphan metabolic phenotype in the presence of ritonavir.
  
  
  RESULTS
  Low-dose ritonavir (100 mg twice daily) significantly increased the exposure to single-dose desipramine, as reflected in a geometric mean ratio (with ritonavir/without ritonavir) of 1.26 (95% confidence interval, 1.13-1.40) for the desipramine area under the concentration versus time curve from time 0 to infinity (P < .001). Coadministration of low-dose ritonavir did not significantly affect the dextromethorphan/dextrorphan urinary metabolic ratio and did not convert any extensive metabolizer to a poor metabolizer.
  
  
  CONCLUSIONS
  Low-dose ritonavir (100 mg twice daily) exerts a modest inhibitory effect on the activity of CYP2D6 in extensive metabolizers, as assessed with desipramine as the index substrate. This effect was not apparent with the dextromethorphan/dextrorphan metabolic ratio as an indicator for CYP2D6 activity. It is expected that the effect of low-dose ritonavir on CYP2D6 will not require standard dose reductions for CYP2D6 substrates.
authors.affiliation: Departments of Clinical Pharmacy and General Internal Medicine, Nijmegen University Centre for Infectious Diseases, Radboud University Nijmegen Medical Centre, 6500 HB Nijmegen, the Netherlands. R.Aarnoutse@akf.umcn.nl
authors.forename: Rob E
authors.initials: RE
authors.lastname: Aarnoutse
authors.forename: Johanneke
authors.initials: J
authors.lastname: Kleinnijenhuis
authors.forename: Peter P
authors.initials: PP
authors.lastname: Koopmans
authors.forename: Daan J
authors.initials: DJ
authors.lastname: Touw
authors.forename: Jaap
authors.initials: J
authors.lastname: Wieling
authors.forename: Yechiel A
authors.initials: YA
authors.lastname: Hekster
authors.forename: David M
authors.initials: DM
authors.lastname: Burger
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D019540:Area Under Curve; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics / Q000378:metabolism*; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D003891:Desipramine / Q000008:administration & dosage / Q000493:pharmacokinetics; D003915:Dextromethorphan / Q000652:urine; D003917:Dextrorphan / Q000652:urine; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D017320:HIV Protease Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D019438:Ritonavir / Q000008:administration & dosage / Q000493:pharmacokinetics*; D013997:Time Factors
chemical_list: D065690:Cytochrome P-450 CYP2D6 Inhibitors; D017320:HIV Protease Inhibitors; D003917:Dextrorphan; D003915:Dextromethorphan; D019389:Cytochrome P-450 CYP2D6; D019438:Ritonavir; D003891:Desipramine