       Document 0715
 DOCN  M9620715
 TI    Pharmacokinetic optimisation of antiretroviral therapy in patients with
       HIV infection.
 DT    9602
 AU    Stretcher BN; Department of Pathology and Laboratory Medicine,
       University of; Cincinnati College of Medicine, Ohio, USA.
 SO    Clin Pharmacokinet. 1995 Jul;29(1):46-65. Unique Identifier : AIDSLINE
       MED/96065832
 AB    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.
 DE    Aging/METABOLISM  Antineoplastic Agents/ADMINISTRATION &
       DOSAGE/PHARMACOKINETICS/  THERAPEUTIC USE  Antiviral
       Agents/BLOOD/*PHARMACOKINETICS/THERAPEUTIC USE
       Didanosine/BLOOD/PHARMACOKINETICS/THERAPEUTIC USE  Drug Interactions
       Guidelines  Human  HIV Infections/*DRUG THERAPY/METABOLISM
       Phosphorylation  Racial Stocks  Sex Characteristics
       Stavudine/BLOOD/PHARMACOKINETICS/THERAPEUTIC USE
       Zalcitabine/BLOOD/PHARMACOKINETICS/THERAPEUTIC USE
       Zidovudine/BLOOD/PHARMACOKINETICS/THERAPEUTIC USE  JOURNAL ARTICLE
       REVIEW  REVIEW, TUTORIAL

       SOURCE: National Library of Medicine.  NOTICE: This material may be
       protected by Copyright Law (Title 17, U.S.Code).

