Intra-individual variability in lopinavir plasma trough concentrations supports therapeutic drug monitoring.

Abstract

Interindividual variability in protease inhibitor (PI) plasma concentrations is widely recognized, and partly explains the different degree of inhibition of HIV replication provided by the same antiretroviral regimens in different patients. The monitoring of plasma antiretroviral concentrations, or therapeutic drug monitoring (TDM), is currently being introduced into some clinical practice. However, the debate is still ongoing about the value of drug dose adjustments after TDM to achieve concentrations sufficient for suppressing HIV replication [1,2]. One of the arguments raised against TDM is that marked intrapatient variability means that a single concentration is of limited value. In relation to the intra-individual variability of PI, although a few studies [2–5] have been published, additional data are required to be able to address this issue. It is primarily environmental factors (internal, external) that lead to significant intra-individual variability of drug concentrations in a controlled setting. In addition, in the clinical setting, inaccurate reporting of the time of drug intake, non-compliance with food requirements and, more generally, with regular drug intake, are all key factors accounting for significant variations in plasma PI levels. As a consequence, a single drug measurement may be insufficient for a reliable evaluation of patient exposure to a drug, and dose adjustements based on a single evaluation could be inappropriate. Ideally, a patient should take an observed drug dose to ensure an accurate interval between drug intake and blood sampling, but this complicates the applicability of TDM to general clinical practice. The aim of this study was to investigate the intra-individual variability of lopinavir trough concentrations (Ctrough) in HIV-positive patients attending an outpatient clinic when the dose intake was not witnessed. Twenty-five HIV-infected patients (22 men, three women; median age 42 years, range 29–51) on a lopinavir/ritonavir plus two nucleoside reverse transcriptase inhibitors-containing regimen were studied prospectively over a median period of 18 months (range 14–22). Blood samples (7 ml) were obtained before the morning dose of lopinavir/ritonavir. For each patient five to nine replicate samples were obtained over the follow-up period. Lopinavir plasma levels were measured by a high-performance liquid chromatography–mass spectrometer system within the University of Liverpool TDM Programme [6]. Three patients were naive to antiretroviral agents, seven were on their second PI-containing regimen, and 15 were multi-experienced. The overall previous PI intake was 30 months (range 19–52). The median CD4 cell count was 204 cells/mm3 (range 94–433) at baseline and 280 cells/mm3 (range 170–601) at the end of follow-up. The plasma HIV-RNA level was 101 500 copies/ml (range 6900–1 000 000) at baseline and was undetectable in 16 out of 25 subjects at the end of follow-up; the remaining nine subjects had a median viral load of 620 copies/ml (range 100–7900). A total of 143 samples were analysed and the median lopinavir Ctrough considering all 25 patients ranged from 1832 to 11 362 ng/ml (median 5365). The median coefficient of variation of intrapatient variability was 35% (range 15–54) (Table 1) [7].Table 1: Lopinavir trough concentrations measured over 18 months (range 14–22) in 25 HIV-infected patients.The variability determined for lopinavir is of the same order of magnitude as that reported for nelfinavir and amprenavir when administered without ritonavir boosting [2,3]. Although recognizing that there are differences in concentrations in individual consecutive samples, the intra-individual variability determined in most subjects gives some degree of confidence that TDM can be applied to lopinavir (and PI in general) in certain settings. Whereas the overall performance of TDM may be further improved by better patient education, especially in terms of adherence, it does seem that even only a few determinations of plasma concentrations may by be representative of individual exposure to PI, and may thus form the basis for dose adjustment.