Concentration effect relationship of CYP3A inhibition by ritonavir in humans

• Published in: European journal of clinical pharmacology Vol. 69; no. 10; pp. 1795 - 1800
• Main Authors: Eichbaum, Christine, Cortese, Marianna, Blank, Antje, Burhenne, Jürgen, Mikus, Gerd
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.10.2013; Springer; Springer Nature B.V
• Subjects: Adult; Antiretroviral drugs; Area Under Curve; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Cytochrome P-450 CYP3A; Cytochrome P-450 CYP3A Inhibitors; Dose-Response Relationship, Drug; Drug dosages; Enzymes; Female; HIV Protease Inhibitors - administration & dosage; HIV Protease Inhibitors - blood; HIV Protease Inhibitors - pharmacology; Humans; Male; Medical sciences; Midazolam - administration & dosage; Midazolam - blood; Midazolam - pharmacology; Middle Aged; Nontherapeutic Human Experimentation; Pharmacokinetics and Disposition; Pharmacology; Pharmacology. Drug treatments; Pharmacology/Toxicology; Prescription drugs; Ritonavir - administration & dosage; Ritonavir - blood; Ritonavir - pharmacology; Young Adult; CYP3A; Inhibition; Midazolam; Ritonavir; Human; Antiretroviral agent; Enzyme; Isozyme; Psychotropic; Cytochrome P450; Enzyme inhibitor; Hypnotic; Peptidases; Activity concentration relation; Benzodiazepine derivatives; Hydrolases; Antiviral; Sedative; Protease inhibitor
• ISSN: 0031-6970; 1432-1041; 1432-1041
• DOI: 10.1007/s00228-013-1530-8

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 ID 50 of 3.4 mg. Using the measured ritonavir concentrations an exposure–inhibition effect curve was established with an IC 50 of 600 h pmol/L (AUC 2–4 ). 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.