6th International Workshop on Adverse Drug Reactions and Lipodystrophy in HIV 25–28 October 2004 - Washington, DC, USA

CLINICAL PHARMACOLOGY OF NRTI-TRIPHOSPHATES

Antiviral Therapy 2004; 9(6):L2 (abstract no. P4)

CV Fletcher
Department of Clinical Pharmacy, University of Colorado Health Sciences Center, Denver, Col., USA

Nucleoside analogue reverse transcriptase inhibitors (NRTIs) are the current backbone of virtually all combination antiretroviral therapies for the treatment of HIV infection. NRTIs are actually prodrugs because the active moiety is the triphosphate anabolite that is formed intracellularly. NRTI-triphosphates elicit their anti-HIV effect via the inhibition of HIV reverse transcriptase, and presumably toxicity via the inhibition of mitochondrial DNA polymerase gamma. Therefore, the most informed and rational use of these compounds fundamentally depends upon a quantitative understanding of the clinical pharmacology of intracellular NRTI-triphosphates.

NRTI combinations such as zidovudine and lamivudine are well-documented to act synergistically in terms of antiretroviral activity. The recently demonstrated profound rates of virological failure of certain triple NRTI regimens (such as abacavir, lamivudine and tenofovir DF), however, has demonstrated unanswered questions about the pharmacological basis for NRTI combinations as well as intracellular drug–drug interactions. NRTIs have been extensively used clinically and are considered safe agents with well-described adverse effect profiles. However, serious toxicities including lactic acidaemia±microvesicular hepatic steatosis, pancreatitis, peripheral neuropathy, and lipoatrophy, which have incidence rates up to 15% for lactic acidosis and up to 50% for lipoatrophy, illustrate limited knowledge about risk factors, including patient characteristics associated with NRTI adverse drug reactions. These gaps in our clinical pharmacological knowledge of NRTIs and their pharmacologically active triphosphate moieties exist, to a large degree, due to the challenges of intracellular NRTI-triphosphate quantitation.

Recent advances in analytical methodologies have allowed the generation of new knowledge about clinical pharmacological characteristics of NRTI-triphosphates with findings of, for example, sex and disease state associations with triphosphate formation, and relationships between intracellular NRTI-triphosphate concentrations and virological response. New insights into the clinical pharmacology of NRTI-triphosphates hold promise as a tool to advance the state of HIV therapeutics.

2004-10-25
P4

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