Pharmacokinetic optimisation of antiretroviral therapy in patients with HIV infection.
More than 7 years after the introduction of zidovudine for treatment of HIV infection, little use has been made of the pharmacokinetic properties of this or any of the subsequently approved antiretroviral agents to optimise therapy. This is partly because of the limits of technologies developed to measure clinically relevant forms and concentrations of these drugs, and partly because the clinical community has been slow to recognise the potential benefits of pharmacokinetic optimisation of nucleoside analogue therapy in any disease. Nonetheless, for some of these agents, progress in understanding the relationship between pharmacokinetics and pharmacodynamics has been made. With zidovudine, for example, even though plasma concentrations have little clinical utility, evidence suggests that concentrations of active phosphorylated forms of zidovudine inside target cells are related to disease progression and toxicity. Furthermore, a decreased ability to phosphorylate zidovudine might be a prerequisite for the emergence of zidovudine-resistant HIV strains. Measurements of phosphorylated zidovudine inside cells similarly suggest that 100 mg of oral zidovudine every 8 hours approximates the optimal initial dosage regimen in asymptomatic patients. Increased plasma didanosine concentrations have been associated with several measures of clinical improvement in patients, and may be associated with an increased risk of toxicity as well. For zalcitabine and stavudine, however, the picture is much less clear. Their pharmacokinetic and pharmacodynamic relationships have not been studied in patients. Furthermore, there is insufficient data on the effects of age, gender, race and concurrent underlying conditions on the pharmacokinetics of all of these agents. Mounting evidence suggests that monitoring of these compounds could lead to individually optimised intervention strategies. Given the marginal benefits of therapy with these agents, their proven toxic effects and the lack of proven alternatives, it is critical that the clinical community strive to make the most effective use of these agents in the treatment of their patients.
Stretcher
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Department of Pathology and Laboratory Medicine, University of Cincinnati College of Medicine, Ohio, USA.
D000375:Aging / Q000378:metabolism; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use; D000998:Antiviral Agents / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D016049:Didanosine / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use; D004347:Drug Interactions; D017408:Guidelines as Topic; D015658:HIV Infections / Q000188:drug therapy* / Q000378:metabolism; D006801:Humans; D010766:Phosphorylation; D044469:Racial Groups; D012727:Sex Characteristics; D018119:Stavudine / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use; D016047:Zalcitabine / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use; D015215:Zidovudine / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use
D000970:Antineoplastic Agents; D000998:Antiviral Agents; D015215:Zidovudine; D016047:Zalcitabine; D018119:Stavudine; D016049:Didanosine