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Effect of an Antiretroviral Regimen Containing Ritonavir Boosted Lopinavir on Intestinal and Hepatic CYP3A, CYP2D6 and P‐glycoprotein in HIV‐infected Patients
Author(s) -
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
Publication year - 2008
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1038/sj.clpt.6100452
Subject(s) - ritonavir , lopinavir , cyp3a , pharmacokinetics , pharmacology , p glycoprotein , lopinavir/ritonavir , medicine , cyp2d6 , virology , gastroenterology , biology , viral load , human immunodeficiency virus (hiv) , drug resistance , antiretroviral therapy , multiple drug resistance , cytochrome p450 , microbiology and biotechnology , metabolism
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 AUC dextromethorphan /AUC dextrorphan 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