F2/2 - THE RELATIONSHIP BETWEEN INTRACELLULAR AND PLASMA PHARMACOKINETICS OF NELFINAVIR AND M8 IN HIV INFECTED PATIENTS WITH P-GLYCOPROTEIN EXPRESSION

9^TH EUROPEAN AIDS CONFERENCE (EACS)
1^st EACS RESISTANCE & PHARMACOLOGY WORKSHOP

October 25 - 29, 2003 Warsaw, Poland

4.1 PK and Pharmacodynamics

F2/2 - THE RELATIONSHIP BETWEEN INTRACELLULAR AND PLASMA PHARMACOKINETICS OF NELFINAVIR AND M8 IN HIV INFECTED PATIENTS WITH P-GLYCOPROTEIN EXPRESSION

* Ford J.¹, Hoggard P.G.¹, Meaden E.R.¹, Newton P.², Cuthbertson Z.³, Williams I.², Johnson M.³, Daniels E.⁴, Hsyu P.⁴, Khoo S.H.¹, Back D.J.¹

(1) Department of Pharmacology, University of Liverpool, U.K.,² University College London, U.K.,³ Royal Free Hospital, London, U.K.,⁴ Agouron Pharmaceuticals, San Diego, Chile

Background of Study: The target of ART is HIV infected cells. To understand ART failure, both intracellular (IC) and plasma pharmacokinetics (PK) should be studied. Previously, IC accumulation of PIs, [nelfinavir(NFV)>saquinavir>ritonavir>indinavir] has been reported in vivo. Multidrug resistance transporters, such as P-glycoprotein (P-gp), may lower IC concentrations, thus contributing to sanctuary sites.

Objectives: Study aims were to determine NFV and M8 concentrations in plasma and PBMCs from patients and to relate IC concentrations to P-gp expression.

Methods: Blood samples from 12 patients receiving NFV (1250mg BID) were obtained at 0, 2, 4, 8, 12h. P-gp expression was determined by flow cytometry. Plasma and IC drug concentrations were measured by HPLC-MS/MS. Drug exposure in plasma and cells was expressed as (AUC0-12h).

Results: The median [range] AUC0-12h of NFV in plasma was 38.4µM.h-1 [9.92-89.4] and in cells was 184.1µM.h-1 [40.6-467.4]. Corresponding M8 values were 11.3µM.h-1 [3.69-29.5] and 33.6µM.h-1 [8.80-104.1]. The median ratio of plasma M8/plasma NFV and IC M8/IC NFV was 0.34 and 0.15. The median cellular accumulation of NFV and M8 was 5.30 [2.28-16.2] and 2.32 [1.01-10.7]. There was a correlation between NFV plasma and IC Cmin (R2=0.34; p<0.05), but not between M8 plasma and IC Cmin. NFV and M8 C0h concentrations were higher than C12h. There was no relationship between NFV and M8 accumulation and P-gp expression.

Conclusions: IC concentrations were higher than plasma concentrations for NFV and M8, suggesting lymphocyte accumulation. The mechanism of differential IC accumulation of NFV and M8 is unclear but may reflect affinities for influx transporters or inherent drug characteristics.

Presenting Author: Miss Jennifer Ford, University of Liverpool, 70 Pembroke Place, Block H, First Floor, L69 3GF, Liverpool, United Kingdom, Phone: 00 44 151 794 5565

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