Strategies for control of zidovudine concentrations in serum

Abstract

There are several clinical scenarios in which knowledge of zidovudine disposition may be important. This study evaluated the clinical utility of pharmacokinetic parameters for zidovudine derived from sparse serum concentration data obtained in an outpatient setting. Twelve human immunodeficiency virus-infected participants had two serum zidovudine concentration determinations obtained on two different clinic visits, 2 to 38 days apart. Zidovudine concentrations were measured by radioimmunoassay. A one-compartment oral absorption model was used to describe zidovudine disposition. Three different approaches were used to estimate pharmacokinetic parameters: Bayesian estimation with one or two concentrations and least squares with one concentration. The ability of these parameters to predict concentrations measured during the second clinic visit was assessed by calculation of precision and bias and compared with predictions using standard fixed or weight-adjusted parameters. Estimated pharmacokinetic parameters for zidovudine were consistent with literature values; there was no statistically significant difference among the parameters calculated with the three estimation strategies. Absorptive phase concentrations were poorly predicted by all methods (mean percent bias, 157 to 249%; mean percent precision, 389 to 537%). Predictive ability for concentrations obtained in the elimination phase was strikingly improved: mean percent bias, ؊17 to 70%; mean percent precision, 40 to 95%. Bayesian and least-squares estimated parameters were statistically better than fixed-parameter values for predicting concentrations in the elimination phase. These observations provide a modeling framework to determine pharmacokinetic disposition of zidovudine in an individual, screen for the existence of a drug interaction, and conduct concentration-controlled clinical trials.

Influence of the Cytochrome P450 2B6 Genotype on Population Pharmacokinetics of Efavirenz in Human Immunodeficiency Virus Patients

“…The clinical usefulness of patient-specific PK data for antiretrovirals has been evaluated in an effort to develop strategies for monitoring drug exposure in HIV-infected patients (29). The goal of the present study was to investigate the population PK parameters of EFV estimated from TDM data in order to implement them in clinical PK software for dosage optimization.…”

Pharmacological Basis for Concentration-Controlled Therapy with Zidovudine, Lamivudine, and Indinavir

“…Patients were not allowed to eat 1 h before or 2 h after ingestion of their medications since food has been shown to affect absorption of these drugs (3,7,24,26,32,35). Blood samples were also obtained between 2 and 5 h following drug administration at weeks 4, 8, 12, 16, 20, and 24. This time frame was chosen to avoid the absorption phase and obtain postabsorption concentrations within an optimal window, as assessed by D-optimality criteria, as previously described for zidovudine (27).…”

Relationship between exposure to zidovudine and decrease of P24 antigenemia in HIV‐infected patients in monotherapy

“…Zidovudine is no longer given alone in the usual treatment of HIV‐infected patients, but these results, and the important pharmacokinetic and pharmacodynamic variability confirmed here, suggested that low dosage of zidovudine should be avoided and that plasma concentration of zidovudine should be monitored [3,4]. Given the population pharmacokinetic analyses of zidovudine already performed in patients, therapeutic drug monitoring could be done at the beginning of treatment using Bayesian estimation from a small number of individual concentrations [6].…”

“…Indeed, zidovudine must be phosphorylated into the infected cells to inhibit HIV replication [3], and therefore concentration of phosphorylated zidovudine might be more predictive of clinical efficacy. However, routine measurement of phosphorylated zidovudine is not possible as yet, and monitoring of the plasma concentration has been suggested by several authors [4,6]. More recently, two subsequent studies showed the benefit of a concentration‐controlled zidovudine therapy [7,8].…”