Population Pharmacokinetics Study of Recommended Zidovudine Doses in HIV-1-Infected Children

Abstract

The aims of this study were to describe the pharmacokinetics of zidovudine (ZDV) and its biotransformation to its metabolite, 3*-azido-3*-deoxy-5*-glucuronylthymidine (G-ZDV), in HIV-infected children, to identify factors that influence the pharmacokinetics of ZDV, and to compare and evaluate the doses recommended by the World Health Organization (WHO) and the Food and Drug Administration (FDA). ZDV concentrations in 782 samples and G-ZDV concentrations in 554 samples from 247 children ranging in age from 0.5 to 18 years were retrospectively measured. A population pharmacokinetic model was developed with NONMEM software (version 6.2), and the pharmacokinetics of ZDV were best described by a one-compartment model with first-order absorption and elimination. The effect of body weight on the apparent elimination clearance and volume of distribution was significant. The mean population parameter estimates were as follows: absorption rate, 2.86 h ؊1 ; apparent elimination clearance, 89.7 liters · h ؊1 (between-subject variability, 0.701 liters · h ؊1 ); apparent volume of distribution, 229 liters (betweensubject variability, 0.807 liters); metabolic formation rate constant, 12.6 h ؊1 (between-subject variability, 0.352 h ؊1 ); and elimination rate constant of G-ZDV, 2.27 h ؊1 . On the basis of simulations with FDA and WHO dosing recommendations, the probabilities of observing efficient exposures (doses resulting in exposures of between 3 and 5 mg/liter · h) with less adverse events (doses resulting in exposures below 8.4 mg/liter · h) were higher when the FDA recommendations than when the WHO recommendations were followed. In order to improve the FDA recommendations, ZDV doses should be reconsidered for the weight band (WB) of 20 to 40 kg. The most appropriate doses should be decreased from 9 to 8 mg/kg of body weight twice a day (BID) for the WB from 20 to 29.9 kg and from 300 to 250 mg BID for the WB from 30 to 39.9 kg. The highest dose, 300 mg BID, should be started from body weights of 40 kg. Z idovudine (ZDV) was the first antiretroviral drug allowed by the Food and Drug Administration (FDA) and approved for the treatment of children with HIV infection (1). It was the most prescribed monotherapy in children and adults, and currently, ZDV-containing regimens are still recommended as first-line combination regimens for infants and children by the World Health Organization (WHO) (2). However, limited pharmacokinetic (PK) studies have been conducted in children (small size, narrow range of ages and/or body weight, single-dose regimen, and the doses administered were different from the last doses recommended) (3-11).Recommended dosing regimens have changed in recent years. Before 2009, the ZDV dosage was based on the body surface area (BSA). The recommended oral dose was 480 mg/m 2 /day given as 240 mg/m 2 twice daily (BID) or 160 mg/m 2 three times daily (TID) (12). The equivalent weight-based dose of 480 mg/m 2 /day for an average child with a BSA of 1 m 2 and a weight of 32 kg is approximately 15 mg/kg of body wei...

Age‐ and Genotype‐Dependent Variability in the Protein Abundance and Activity of Six Major Uridine Diphosphate‐Glucuronosyltransferases in Human Liver

“…Similarly, in vitro acetaminophen glucuronidation activity is negligible in fetal liver, which gradually increases in neonates and matches adult levels only at 10 years of age . UGT abundance and activity data in children (age 1–12 years) and adolescents were lower than in adults, which are corroborated by literature data on rate of glucuronidation of drugs such as chroramphenicol, morphine, zidovudine, and trifluoperazine …”

“…Solid lines represent mean predictions and the dotted lines are predicted 95 th and 5 th confidence intervals. Once the adult model was validated by comparison with the observed data, ontogeny data of UGT2B7 improved the performance of the neonatal and pediatric models to predict the observed data within 95 th and 5 th percentiles (b vs. c and d vs. e). [Color figure can be viewed at http://cpt-journal.com]…”

“…Visual inspection and statistical analyses were conducted to assess the accuracy of both the neonatal and pediatric population PBPK models. Similar to the adult model, the pediatric PBPK model predictions were determined to be successful if the predicted mean plasma concentration overlapped the observed in vivo values obtained from the literature and were between the predicted 5 th to 95 th percentiles of the plasma concentrations for zidovudine.…”

Maternal and fetal zidovudine pharmacokinetics during pregnancy and labour: too high dose infused at labour?

“…This value has been reported by Panhard et al . and used in others studies . A covariance between CL and V significantly improved the model.…”

“…10 × I C 50 ) were calculated for the fetus during pregnancy and for the neonate with the lower and higher concentrations at delivery. Two other criteria have been defined to interpret the different exposures calculated, the therapeutic range described in adults/children between 3 and 5 mg l −1 h and the exposure associated with a higher risk of toxicity reported in children. Indeed, a mean exposure, from 0 to 24 h (AUC(0,24 h)), greater than 8.4 mg l −1 h was suggested to increase the risk of anaemia by 32% .…”