Effect of an Antiretroviral Regimen Containing Ritonavir Boosted Lopinavir on Intestinal and Hepatic CYP3A, CYP2D6 and P‐glycoprotein in HIV‐infected Patients.
^
Study Design
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. Authors 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.
Study Results
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.
Study Conclusions
Cytochrome P450 3A, CYP2D6, and P‐glycoprotein are profoundly inhibited in patients receiving ritonavir boosted lopinavir. Midazolam is a CYP3A4 substrate; inhibition of CYP3A4 by PIs can lead to increased sedative/hypnotic concentrations and an increased risk of excessive sedation and respiratory depression.
References
Wyen C, Fuhr U, Frank D, Aarnoutse RE, Klassen T, Lazar A, Schmeisser N. Effect of an antiretroviral regimen containing ritonavir boosted lopinavir on intestinal and hepatic cyp3a, cyp2d6 and p‐glycoprotein in hiv‐infected patients. Clinical Pharmacology And Therapeutics. 2008; 1: 75-82.
icon on your home screen.