Lopinavir/ritonavir pharmacokinetics in HIV/HCV-coinfected patients with or without cirrhosis.
Liver disease may alter the pharmacokinetics of antiretrovirals and produce changes in plasma protein binding. The aim was to evaluate the pharmacokinetics of total and unbound lopinavir (LPV) in HIV-infected patients with and without hepatitis C virus (HCV) coinfection. Fifty-six HIV+ patients receiving lopinavir/ritonavir (LPV/r) (group I = 24 controls; II = 23 HIV/HCV-coinfected; III = 9 cirrhotic HIV/HCV-coinfected) were included. Total (n = 56) and unbound (n = 36) LPV pharmacokinetic parameters were determined at steady-state using validated high-performance liquid chromatography with ultraviolet detection and high-performance liquid chromatography-tandem mass spectrometry methods, respectively. Pharmacokinetic parameters (plasma concentration just before drug administration, peak concentrations in plasma, times to maximum plasma concentration, areas under the plasma concentration-time curve from 0 to 12 hours, and CL/F/kg) of both total and unbound LPV were calculated by standard noncompartmental methods and differences among groups evaluated (Kruskal-Wallis test).LPV apparent oral clearance normalized to body weight (median, interquartile range) was 55 (40-68), 59 (44-69), and 71 (53-78) mL/h/kg for groups I, II, and III, respectively (II vs. I, P = 0.52; III vs. I, P = 0.16). The areas under the plasma concentration-time curve from 0 to 12 hours were 110.4 (80.9-135.2), 103.4 (85.5-131.3), and 92.8 (87.4-116.3) microg h/mL for groups I, II, and III, respectively (II vs. I, P = 0.68; III vs. I, P = 0.71). Chronic liver impairment produced a slight, although not significant, decrease in plasma protein binding. The free-fraction of LPV increased ( approximately 21%) from 0.97% (0.80-1.06) in HIV+/HCV- patients to 1.18% (0.89-1.65) in HIV/HCV+ cirrhotic patients. The apparent oral clearance of unbound LPV (CLu/F/kg) in cirrhotic patients did not change significantly, supporting the concept that the clearance of unbound LPV in liver disease is not affected after being inhibited by low-dose ritonavir co-administration.LPV total and unbound pharmacokinetics were not affected by hepatic impairment, suggesting that no adjustment of LPV/r dose is required for HIV/HCV-coinfected patients with and without cirrhosis and moderate impairment of liver function.
II Department of Infectious Diseases - L. Sacco Hospital, Milan, Italy. v.micheli@hsacco.it
Valeria
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Micheli
Mario
M
Regazzi
Laura
L
Dickinson
Paola
P
Meraviglia
Paola
P
Villani
Saye H
SH
Khoo
Paolo
P
Viganò
Laura
L
Cordier
Maria
M
Cusato
Piergiorgio
P
Duca
Giovanna
G
Orlando
Giuliano
G
Rizzardini
David J
DJ
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Antonietta
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Cargnel
D000328:Adult; D019540:Area Under Curve; D001835:Body Weight / Q000502:physiology; D018791:CD4 Lymphocyte Count; D002851:Chromatography, High Pressure Liquid; D005260:Female; D015658:HIV Infections / Q000150:complications / Q000378:metabolism*; D017320:HIV Protease Inhibitors / Q000493:pharmacokinetics*; D006526:Hepatitis C / Q000150:complications / Q000378:metabolism*; D006801:Humans; D008103:Liver Cirrhosis / Q000000981:diagnostic imaging / Q000378:metabolism; D008111:Liver Function Tests; D061466:Lopinavir; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D011744:Pyrimidinones / Q000493:pharmacokinetics*; D012307:Risk Factors; D019438:Ritonavir / Q000493:pharmacokinetics*; D013056:Spectrophotometry, Ultraviolet; D014462:Ultrafiltration; D014463:Ultrasonography
D017320:HIV Protease Inhibitors; D011744:Pyrimidinones; D061466:Lopinavir; D019438:Ritonavir