AEGiS-Glasgow [PL6.3b] Intracellular and plasma pharmacokinetics of saquinavir , atazanavir and ritonavir (SQV/ATV/r) 1600/200/100mg administered once daily in HIV infected patients/TI

Seventh International Congress on Drug Therapy in HIV Infection

Glasgow, UK - 14-17 November 2004

[PL6.3] Intracellular and plasma pharmacokinetics of saquinavir , atazanavir and ritonavir (SQV/ATV/r) 1600/200/100mg administered once daily in HIV infected patients/TI

Int Cong Drug Therapy HIV 2004 Nov 14-18;7:Abstract No. PL6.3b

Jennifer Ford¹, Marta Boffito², Adrian Wildfire², Andrew Hill³, David Back¹, Saye Khoo¹, Mark Nelson², Graeme Moyle², Brian Gazzard², Anton Pozniak²
¹Department of Pharmacology and Therapeutics, University of Liverpool, Liverpool; ²PK Research Ltd, St Stephen's Centre, Chelsea and Westminster Hospital, London; ³Roche Products Ltd, Hertfordshire, Welwyn Garden City, UK

PURPOSE OF THE STUDY: Previously, intracellular (IC) accumulation of PIs has been reported in vivo [nelfinavir>saquinavir (SQV)>lopinavir+ritonavir (RTV)>indinavir]. Here we report plasma and IC levels of atazanavir (ATV) when co-administered with SQV and RTV. Multidrug resistance transporters may provide a mechanism for reducing IC concentrations.

METHODS: To determine IC and plasma SQV, ATV and RTV concentrations in PBMCs in vivo, blood samples from 12 HIV patients receiving SQV/ATV/r 1600/200/100mg once daily were collected (2, 6, 12 and 24h). Plasma and IC concentrations were measured by HPLC-MS/MS and exposure expressed as area under concentration time curve (AUC0-24h). Ratio of cellular AUC0-24h/plasma AUC0-24h was calculated to determine accumulation. Lymphocyte P-gp, BCRP and MRP1 expression was determined.

SUMMARY OF RESULTS: In vivo accumulation of SQV, ATV and RTV in PBMCs gave accumulation ratios of 4.9, 1.2 and 1.7, respectively. Median AUC0-24h of SQV in plasma was 24.9mg.h.L-1 and in cells was 127.0mg.h.L-1. Corresponding ATV values were 25.8mg.h.L-1 and 30.1mg.h.L-1 and RTV values were 6.4mg.h.L-1 and 11.6mg.h.L-1. However, no relationship between SQV, ATV or RTV accumulation and P-gp, MRP1 or BCRP expression was observed.

CONCLUSIONS: IC concentrations were higher than plasma concentrations for all PIs measured. Mechanisms of IC PI accumulation are unclear but may reflect affinities for influx transporters, since no relationships with efflux transporters were observed.

SESSION 6: RESISTANCE AND PHARMACOKINETICS

2004-11-14
PL6-3b

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