Effect of low-dose ritonavir (100 mg twice daily) on the activity of cytochrome P450 2D6 in healthy volunteers

• Published in: Clinical pharmacology and therapeutics 2005-12, Vol.78 (6), p.664-674
• Main Authors: Aarnoutse, Rob E, Kleinnijenhuis, Johanneke, Koopmans, Peter P, Touw, Daan J, Wieling, Jaap, Hekster, Yechiel A, Burger, David M
• Format: Article
• Language: English
• Subjects: Adolescent; Adult; Aged; Area Under Curve; Biological and medical sciences; Cytochrome P-450 CYP2D6 - genetics; Cytochrome P-450 CYP2D6 - metabolism; Cytochrome P-450 CYP2D6 Inhibitors; Desipramine - administration & dosage; Desipramine - pharmacokinetics; Dextromethorphan - urine; Dextrorphan - urine; Dose-Response Relationship, Drug; Drug Administration Schedule; Heterozygote; HIV Protease Inhibitors - administration & dosage; HIV Protease Inhibitors - pharmacokinetics; Homozygote; Humans; Male; Medical sciences; Middle Aged; Pharmacology. Drug treatments; Ritonavir - administration & dosage; Ritonavir - pharmacokinetics; Time Factors
• ISSN: 0009-9236; 1532-6535
• DOI: 10.1016/j.clpt.2005.09.001

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