PURPOSE: To investigate the dose and concentration dependency of CYP3A inhibition by ritonavir using the established limited sampling strategy with midazolam for CYP3A activity. METHODS: An open, fixed-sequence study was carried out in 12 healthy subjects. Single ascending doses of ritonavir (0.1-300 mg) were evaluated for CYP3A inhibition in two cohorts using midazolam as a marker substance. RESULTS:Ritonavir administered as a single oral dose produced a dose-dependent CYP3A inhibition with an ID50 of 3.4 mg. Using the measured ritonavir concentrations an exposure-inhibition effect curve was established with an IC50 of 600 h pmol/L (AUC2-4). Over the ritonavir dose range studied non-linear exposure of ritonavir was observed. CONCLUSIONS:Ritonavir shows a dose and concentration effect relationship of CYP3A inhibition. In addition, a proposed auto-inhibition of ritonavir metabolism resulted in a non-linear exposure of ritonavir with sub-proportional concentrations at low doses. A time-dependent CYP3A activity may result when inhibitors of CYP3A with short elimination half-lives are used.
RCT Entities:
PURPOSE: To investigate the dose and concentration dependency of CYP3A inhibition by ritonavir using the established limited sampling strategy with midazolam for CYP3A activity. METHODS: An open, fixed-sequence study was carried out in 12 healthy subjects. Single ascending doses of ritonavir (0.1-300 mg) were evaluated for CYP3A inhibition in two cohorts using midazolam as a marker substance. RESULTS:Ritonavir administered as a single oral dose produced a dose-dependent CYP3A inhibition with an ID50 of 3.4 mg. Using the measured ritonavir concentrations an exposure-inhibition effect curve was established with an IC50 of 600 h pmol/L (AUC2-4). Over the ritonavir dose range studied non-linear exposure of ritonavir was observed. CONCLUSIONS:Ritonavir shows a dose and concentration effect relationship of CYP3A inhibition. In addition, a proposed auto-inhibition of ritonavir metabolism resulted in a non-linear exposure of ritonavir with sub-proportional concentrations at low doses. A time-dependent CYP3A activity may result when inhibitors of CYP3A with short elimination half-lives are used.
Authors: D J Greenblatt; L L von Moltke; J S Harmatz; A L Durol; J P Daily; J A Graf; P Mertzanis; J L Hoffman; R I Shader Journal: J Acquir Immune Defic Syndr Date: 2000-06-01 Impact factor: 3.731
Authors: Oscar Quintela; Angelines Cruz; Marta Concheiro; Ana de Castro; Manuel López-Rivadulla Journal: Rapid Commun Mass Spectrom Date: 2004 Impact factor: 2.419
Authors: Jang-Ik Lee; Diego Chaves-Gnecco; Janet A Amico; Patricia D Kroboth; John W Wilson; Reginald F Frye Journal: Clin Pharmacol Ther Date: 2002-12 Impact factor: 6.875
Authors: Kerry E Culm-Merdek; Lisa L von Moltke; Lu Gan; Kelly A Horan; Robyn Reynolds; Jerold S Harmatz; Michael H Court; David J Greenblatt Journal: Clin Pharmacol Ther Date: 2006-02-07 Impact factor: 6.875
Authors: Nicolas Hohmann; Franziska Kocheise; Alexandra Carls; Jürgen Burhenne; Johanna Weiss; Walter E Haefeli; Gerd Mikus Journal: Clin Pharmacokinet Date: 2016-12 Impact factor: 6.447
Authors: Yomna M Nassar; Nicolas Hohmann; Gerd Mikus; Charlotte Kloft; Robin Michelet; Katharina Gottwalt; Andreas D Meid; Jürgen Burhenne; Wilhelm Huisinga; Walter E Haefeli Journal: Clin Pharmacokinet Date: 2022-10-04 Impact factor: 5.577
Authors: Gerd Mikus; Kathrin I Foerster; Theresa Terstegen; Cathrin Vogt; André Said; Martin Schulz; Walter E Haefeli Journal: Dtsch Arztebl Int Date: 2022-04-15 Impact factor: 8.251
Authors: Manuel Battegay; Parham Sendi; Catia Marzolini; Felix Stader; Marcel Stoeckle; Fabian Franzeck; Adrian Egli; Stefano Bassetti; Alexa Hollinger; Michael Osthoff; Maja Weisser; Caroline E Gebhard; Veronika Baettig; Julia Geenen; Nina Khanna; Sarah Tschudin-Sutter; Daniel Mueller; Hans H Hirsch Journal: Antimicrob Agents Chemother Date: 2020-08-20 Impact factor: 5.191