Pharmacokinetics and Drug Disposition
Clinical Pharmacology & Therapeutics (2005) 78, 664–674; doi: 10.1016/j.clpt.2005.09.001
Effect of low-dose ritonavir (100 mg twice daily) on the activity of cytochrome P450 2D6 in healthy volunteers*
Rob E. Aarnoutse PharmD, PhD1,2,3, Johanneke Kleinnijenhuis MSc1,2,3, Peter P. Koopmans MD, PhD1,2,3, Daan J. Touw PharmD, PhD1,2,3, Jaap Wieling PhD1,2,3, Yechiel A. Hekster PharmD, PhD1,2,3 and David M. Burger PharmD, PhD1,2,3
- 1Departments of Clinical Pharmacy and General Internal Medicine and Nijmegen University Centre for Infectious Diseases, Radboud University Nijmegen Medical Centre, Nijmegen
- 2The Hague Hospitals Central Pharmacy, The Hague
- 3Xendo Drug Development Services, Groningen.
Correspondence: Rob E. Aarnoutse, PharmD, PhD, Department of Clinical Pharmacy, Radboud University Nijmegen Medical Centre, PO Box 9101, 533 KF, 6500 HB, Nijmegen, The Netherlands. E-mail: R.Aarnoutse@akf.umcn.nl
*This work was financed by the Department of Clinical Pharmacy, Radboud University Nijmegen Medical Centre.
Received 25 March 2005; Accepted 6 September 2005.
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.
