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Development
and Validation of a Population Pharmacokinetic Model for Ritonavir
The aim of
this study was to develop and validate a population pharmacokinetic
model of ritonavir, used as an antiviral agent or as a booster,
in a large patient population and to identify factors influencing
its pharmacokinetics.
Ambulatory
HIV-1-infected patients from the outpatient clinic of the Slotervaart
Hospital, Amsterdam, the Netherlands, who were being treated with
a ritonavir-containing regimen were included. During regular visits,
blood samples were collected for the determination of ritonavir
plasma concentrations and several clinical chemistry parameters.
Furthermore,
complete pharmacokinetic curves were available in some patients.
Single and multiple compartment models with zero-order and first-order
absorption, with and without absorption lag-time, with linear and
nonlinear elimination were tested, using nonlinear mixed effect
modeling (NONMEM).
Pharmacokinetic
parameters and inter-individual, inter-occasion and residual variability
were estimated. In addition, the influence of several factors (e.g.
patient characteristics, co-medication) on the pharmacokinetics
of ritonavir was explored.
Results
From 186 patients
505 ritonavir plasma concentrations at a single time-point and 55
full pharmacokinetic profiles were available, resulting in a database
of 1228 plasma ritonavir concentrations.
In total 62%
of the patients used ritonavir as a booster
of their protease inhibitor-containing antiretroviral regimen.
First order
absorption in combination with one-compartment disposition best
described the pharmacokinetics of ritonavir.
Clearance,
volume of distribution and absorption rate constant were 10.5 l
h(-1) prediction interval, 96.6 l and 0.871 h(-1), respectively,
with 38.3%, 80.0% and 169% inter-individual variability, respectively.
The inter-occasion
variability in the apparent bioavailability was 59.1%.
The concomitant
use of lopinavir resulted in a 2.7-fold increase in the clearance
of ritonavir (P value < 0.001).
No patient’s
characteristics influenced the pharmacokinetics of ritonavir.
Conclusions
In conclusion,
the authors write, “The pharmacokinetic parameters of ritonavir
were adequately described by our population pharmacokinetic model.
Concomitant use of the protease inhibitor lopinavir (Kaletra)
strongly influenced the pharmacokinetics of ritonavir. The model
has been validated and can be used for further investigation of
the interaction between ritonavir and other protease inhibitors.
Slotervaart
Hospital, Department of Pharmacy & Pharmacology, Amsterdam,
the Netherlands.
02/04/05
Reference
B S Kappelhoff and others. Development and validation of a population
pharmacokinetic model for ritonavir used as a booster or as an antiviral
agent in HIV-1-infected patients. British Journal of Clinical
Pharmacology 59(2): 174-182. February 2005.
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