Fifth International Congress Drug Therapy in HIV Infection 22-26 October, 2000 Glasgow, UK

KEY PHARMACOLOGICAL ISSUES IN HIV THERAPY

D. Back
Department of Pharmacology & Therapeutics, University of Liverpool, Ashton Street, Liverpool L69 3GE, UK

Int Cong Drug Therapy HIV 2000 Oct 22-26;5:Abstract No. PL8.1
AIDS 2000, Oct 22-26;14(Suppl. 4); S10

Important factors in treatment success are the optimisation of existing therapies alongside the development of new drugs, particularly those acting against novel targets. Improving the ‘benefit to risk’ ratio is a key objective.

It is likely that nucleoside reverse transcriptase inhibitors (NRTIs) will remain the backbone of therapy for the next few years. It is therefore important that we do not think with these ‘older drugs’ that we know all that there is to know. There are still important pharmacological issues to unravel. The pharmacology of NRTIs is complex because of the intracellular activation to the triphosphate and there is a paucity of clinical data in this area primarily due to the complex assay technology. Key studies in progress in various laboratories include: intracellular half life data for different NRTIs, which will impact on thinking re once daily dosing; interaction studies with ribavirin (there is an in vitro interaction with zidovudine but is this relevant in vivo?), mycophenolate (potential beneficial interaction with abacavir) and hydroxyurea.

Much current research aims to improve the long-term therapeutic efficacy of PI-containing regimens. A main focus of this has been to improve PI bioavailability by co-administration with ritonavir. The aim is to give plasma concentrations of non-protein bound drug which are in excess of the IC₅₀ or IC95 of both wild-type and mutant virus. With the growing use of the term ‘Inhibitory Quotient’ (C_min/IC₅₀) to compare different PI combinations it is important to recognise both the strengths and limitations of this approach. While much important data can be generated from looking at plasma pharmacokinetics (PK), and relating PK to phenotype, there is still the need to look beyond plasma to sanctuary sites if we are to address the problem of why some patients are failing therapy regardless of the treatment they are on. The bulk of HIV is contained within and replicates in cells. We, and others, have in recent years acquired expertise in evaluating cellular efflux transporters such as P-glycoprotein (P-gp) and multi-drug resistance protein (MRP) using cell culture systems, RT-PCR and flow cytometric analysis of both transporter expression and function. The role of PIs and NNRTIs as substrates/inhibitors of these various proteins is being characterised.

Finally if we are to understand the complex mechanisms of mitochondrial toxicity or drug hypersensitivity which have emerged as concerns for HIV therapy then basic and clinical pharmacology must be part of the armamentarium to tackle these and related issues.

Presenting author: D. Back

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2000-10-22
PL8-1

Originally published in AIDS Volume 14, Supplement 4 and hosted with permission of the publisher Lippincott Williams & Wilkins, 250 Waterloo Road, London, SE1 8RD, UK. Tel: +44 (0)20 7981 0700 Fax: +44 (0) 7981 0701

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