Clinical Pharmacokinetics of Zidovudine

Abstract

The battle against the acquired immune deficiency syndrome (AIDS) is now into its second decade, and substantial advancements have been made in our understanding of the complex life cycle of, and the immunopathology associated with, human immunodeficiency virus (HIV) infection, as well as of the drugs used to modify the course of disease. Zidovudine was the first agent approved for treatment of HIV disease, and since its widespread availability in 1987 the pharmacokinetic disposition and clinical effects of zidovudine have been extensively evaluated. This article reviews the absorption, distribution, metabolism and elimination characteristics of zidovudine, focusing on more recent information. In addition, factors that may or may not affect zidovudine disposition are discussed. These include selected drug interactions and concomitant disease states such as renal and hepatic insufficiency. Issues such as bodyweight normalisation, maternal-fetal transfer, pregnancy and intracellular phosphorylation are discussed in relation to the pharmacokinetics and clinical efficacy of zidovudine. Finally, information regarding the clinical pharmacodynamics of zidovudine is presented. This includes possible relationships between zidovudine pharmacokinetics and markers of efficacy and toxicity, and the significance of linking pharmacokinetic and pharmacodynamic information.

Development of an Optimized Dose for Coformulation of Zidovudine with Drugs That Select for the K65R Mutation Using a Population Pharmacokinetic and Enzyme Kinetic Simulation Model

“…However, the population enzymology component of the model was limited by the availability of only one data set each, describing the phosphorylation potential (V max ) for TK 1 and TMPK, respectively, in the PBM cells of infected subjects following ex vivo stimulation (48,49). These studies indicated substantial variances in the respective V max values between HIV-infected individuals.…”

“…Like other NRTI, ZDV undergoes three intracellular phosphorylation steps to form the active ZDV-5Ј-triphosphate (ZDV-TP), which inhibits wild-type HIV-1 RT with a median inhibitory concentration of about 0.035 M (72). The single-dose plasma pharmacokinetics of ZDV have been well described in HIV-1-infected individuals following intravenous and oral administration (1,10,20,34,65,78,90).…”

In vitro interaction between Zidovudine and some adsorptive antacids

“…It is also metabolised in the liver, mainly to the inactive glucuronide and is excreted in the urine as unchanged drug and metabolite. 7 Drug interactions have become an increasingly complex challenge for providers treating patients with HIV infection. Despite intense research in many areas of HIV infection, there is often a lack of formal drug interaction studies with HIV medications making providers to often rely on their own clinical judgment and to predict drug interactions without supporting data.…”

InforMatrix Nucleoside/Nucleotide Reverse Transcriptase Inhibitors “Backbones”

“…The drug may theoretically show interactions with a large number of drugs which are also excreted through glucuronidation, like aspirin, NSAIDs, penicillins and oxazepam. Very limited data on the relevance of these possible interactions is available (95). The bioavailability of zidovudine may be decreased to a limited extent (22%) by simultaneouse intake with food (96).…”