Effect of an antiretroviral regimen containing ritonavir boosted lopinavir on intestinal and hepatic CYP3A, CYP2D6 and P-glycoprotein in HIV-infected patients.
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.
Wyen
C
C
Department of Internal Medicine, Hospital of the University of Cologne, Köln, Germany.
Fuhr
U
U
Frank
D
D
Aarnoutse
R E
RE
Klaassen
T
T
Lazar
A
A
Seeringer
A
A
Doroshyenko
O
O
Kirchheiner
J C
JC
Abdulrazik
F
F
Schmeisser
N
N
Lehmann
C
C
Hein
W
W
Schömig
E
E
Burger
D M
DM
Fätkenheuer
G
G
Jetter
A
A
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism*; D000328:Adult; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics / Q000378:metabolism*; D051544:Cytochrome P-450 CYP3A / Q000235:genetics / Q000378:metabolism*; D004357:Drug Synergism; D005260:Female; D015658:HIV Infections / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D017320:HIV Protease Inhibitors / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000187:drug effects / Q000201:enzymology; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D061466:Lopinavir; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D011744:Pyrimidinones / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics; D019438:Ritonavir / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D017320:HIV Protease Inhibitors; D011744:Pyrimidinones; D061466:Lopinavir; D019389:Cytochrome P-450 CYP2D6; D051544:Cytochrome P-450 CYP3A; D019438:Ritonavir