Effect of an Antiretroviral Regimen Containing Ritonavir Boosted Lopinavir on Intestinal and Hepatic CYP3A, CYP2D6 and P-glycoprotein in HIV-infected Patients

• Published in: Clinical pharmacology and therapeutics 2008-07, Vol.84 (1), p.75-82
• Main Authors: Wyen, C, Fuhr, U, Frank, D, Aarnoutse, RE, Klaassen, T, Lazar, A, Seeringer, A, Doroshyenko, O, Kirchheiner, JC, Abdulrazik, F, Schmeisser, N, Lehmann, C, Hein, W, Schömig, E, Burger, DM, Fätkenheuer, G, Jetter, A
• Format: Article
• Language: English
• Subjects: Adult; ATP-Binding Cassette, Sub-Family B, Member 1 - genetics; ATP-Binding Cassette, Sub-Family B, Member 1 - metabolism; Biological and medical sciences; Cytochrome P-450 CYP2D6 - genetics; Cytochrome P-450 CYP2D6 - metabolism; Cytochrome P-450 CYP3A - genetics; Cytochrome P-450 CYP3A - metabolism; Drug Synergism; Female; HIV Infections - drug therapy; HIV Infections - genetics; HIV Infections - metabolism; HIV Protease Inhibitors - administration & dosage; HIV Protease Inhibitors - blood; HIV Protease Inhibitors - pharmacokinetics; Human viral diseases; Humans; Immunodeficiencies; Immunodeficiencies. Immunoglobulinopathies; Immunopathology; Infectious diseases; Intestines - drug effects; Intestines - enzymology; Intestines - metabolism; Liver - drug effects; Liver - enzymology; Liver - metabolism; Lopinavir; Male; Medical sciences; Middle Aged; Pharmacology. Drug treatments; Prospective Studies; Pyrimidinones - administration & dosage; Pyrimidinones - blood; Pyrimidinones - pharmacokinetics; Ritonavir - administration & dosage; Ritonavir - blood; Ritonavir - pharmacokinetics; Viral diseases; Viral diseases of the lymphoid tissue and the blood. Aids
• ISSN: 0009-9236; 1532-6535
• DOI: 10.1038/sj.clpt.6100452

This study aimed to quantify the inhibition of cytochrome P450 (CYP3A), CYP2D6, and P‐glycoprotein in human immunodeficiency virus (HIV)‐infected patients receiving an antiretroviral therapy (ART) containing ritonavir boosted lopinavir, and to identify factors influencing ritonavir and lopinavir pharmacokinetics. We measured activities of CYP3A, CYP2D6, and P‐glycoprotein in 28 patients before and during ART using a cocktail phenotyping approach. Activities, demographics, and genetic polymorphisms in CYP3A, CYP2D6, and P‐glycoprotein were tested as covariates. Oral midazolam clearance (overall CYP3A activity) decreased to 0.19‐fold (90% confidence interval (CI), 0.15–0.23), hepatic midazolam clearance and intestinal midazolam availability changed to 0.24‐fold (0.20–0.29) and 1.12‐fold (1.00–1.26), respectively. In CYP2D6 extensive metabolizers, the plasma ratio AUCdextromethorphan/AUCdextrorphan increased to 2.92‐fold (2.31–3.69). Digoxin area under the curve (AUC)0–12 (P‐glycoprotein activity) increased to 1.81‐fold (1.56–2.09). Covariates had no major influence on lopinavir and ritonavir pharmacokinetics. In conclusion, CYP3A, CYP2D6, and P‐glycoprotein are profoundly inhibited in patients receiving ritonavir boosted lopinavir. The covariates investigated are not useful for a priori dose selection. Clinical Pharmacology & Therapeutics (2008); 84, 1, 75–82 doi:10.1038/sj.clpt.6100452