Pharmacokinetics of Lopinavir/ritonavir (Kaletra) in HIV-HCV Coinfected Patients
with or without Liver Cirrhosis
Liver
disease may alter the pharmacokinetics of antiretroviral
agents and lead to changes in plasma protein binding of drugs. The aim of
the current study, published in the June 2008 issue of Therapeutic Drug Monitoring,
was to evaluate the pharmacokinetics of total and unbound lopinavir in HIV-infected
patients with and without hepatitis
C virus (HCV) coinfection. •
Group I = 24
control subjects without HCV;
•
Group II =
23 HIV-HCV coinfected patients;
•
Group III =
9 cirrhotic HIV-HCV coinfected patients.
Total
(n = 56) and unbound (n = 36) lopinavir 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) of both total and unbound lopinavir were calculated
using standard non-compartmental methods and differences among the groups were
evaluated. Results
•
Lopinavir apparent
oral clearance normalized to body weight (median, interquartile range) was 55
(40-68) mL/h/kg for Group I, 59 (44-69) mL/h/kg for Group II, and 71 (53-78) mL/h/kg
for Groups III (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)
microgram h/mL for Group I, 103.4 (85.5-131.3) microgram h/mL for Group II, and
92.8 (87.4-116.3) microgram h/mL for Group III (II vs I, P = 0.68; III vs I, P
= 0.71).
•
Chronic liver
impairment was associated with a slight, though not significant, decrease in plasma
protein binding.
•
The free fraction
of lopinavir increased by approximately 21%, from 0.97% in patients without HCV
to 1.18% in HIV-HCV coinfected cirrhotic patients.
According
to the study authors, "The apparent oral clearance of unbound lopinavir in
cirrhotic patients did not change significantly, supporting the concept that the
clearance of unbound lopinavir in liver disease is not affected after being inhibited
by low-dose ritonavir co-administration." They
concluded, "Lopinavir total and unbound pharmacokinetics were not affected
by hepatic impairment, suggesting that no adjustment of lopinavir/ritonavir dose
is required for HIV-HCV coinfected patients with and without cirrhosis and moderate
impairment of liver function." Department
of Infectious Diseases, L. Sacco Hospital, Milan, Italy. 7/25/08 Reference
V Micheli,
M Regazzi, L Dickinson, and others. Lopinavir/ritonavir pharmacokinetics in HIV/HCV-coinfected
patients with or without cirrhosis. Therapeutic Drug Monitoring 30(3): 306-313.
June 2008. (Abstract) |
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