Sixth International Congress Drug Therapy in HIV Infection 17-21 November, 2002 Glasgow, UK

[ABSTRACT:] HIV protease inhibitors (PIs) are substrates for the drug efflux transporters P-glycoprotein and multidrug resistance-associated protein. Inter-individual variation in the expression of these two transporters may therefore affect intracellular PI accumulation in vivo.

The aim of this study was to determine P-glycoprotein and MRP1 expression and LPV and RTV concentrations in the plasma and peripheral blood mononuclear cells of HIV patients receiving Kaletra® as part of combination therapy and to ascertain if any relationships exist between them.

All patients had undetectable plasma viral load (<50 copies/ml) on combination antiretroviral therapy including LPV/RTV (400/100 or 533/133mg bd). Patients (n=12) undergoing treatment with drugs known to be substrates/inhibitors of P-glycoprotein or MRP were excluded from the trial. Venous blood samples (25 ml) were collected at pre-dose and 2, 4, 8 and 12h after supervised drug ingestion. Plasma and intracellular (cell associated) drug concentrations were measured by HPLC-MS/MS. Lymphocyte expression of P-glycoprotein and MRP1 was investigated using immunofluorescence and detected by flow cytometry. The ratio of intracellular AUC_0-12 / plasma AUC_0-12h was calculated to determine the cellular drug accumulation.

The median (range) intracellular/plasma AUC_0-12h of LPV was 1.56 (0.67 – 3.80). A statistically significant relationship was observed (Pearson’s correlation; p=0.0275; CI = -0.88 to -0.09) between the expression of P-glycoprotein and the intracellular accumulation of LPV, with increased P-glycoprotein expression related to a lower intracellular LPV accumulation. A similar trend was also observed with MRP1 expression and LPV accumulation (p=0.119). The median intracellular accumulation of RTV was signifi- cantly higher in these patients (5.28 versus 1.02; p<0.0001) compared to previous studies with patients receiving RTV only. There were weak relationships between P-glycoprotein and MRP expression and RTV accumulation (p=0.095 and p=0.092 respectively).

Although there is marked variability in intracellular and plasma concentrations of both LPV and RTV, increased expression of the efflux transporters, Pglycoprotein and MRP1 on lymphocytes, appears to be associated with lower intracellular accumulation of LPV and RTV in vivo. The increased RTV intracellular accumulation in patients receiving LPV warrants further investigation.

Presenting author: Patrick Hoggard

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1 University of Liverpool, Liverpool, United Kingdom

2 Royal Free and University College Medical School, London, United Kingdom

2002-11-17
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