11 research outputs found
Constructing a representative in-silico population for paediatric simulations: Application to HIV-positive African children
AIMS: Simulations are an essential tool for investigating scenarios in pharmacokinetics-pharmacodynamics. The models used during simulation often include the effect of highly correlated covariates such as weight, height and sex, and for children also age, which complicates the construction of an in silico population. For this reason, a suitable and representative patient population is crucial for the simulations to produce meaningful results. For simulation in paediatric patients, international growth charts from the World Health Organization (WHO) and the Centers for Disease Control and Prevention (CDC) provide a reference, but these may not always be representative for specific populations, such as malnourished children with HIV or acutely unwell children. METHODS: We present a workflow to construct a virtual paediatric patient population using WHO and CDC growth charts, suggest piecewise linear functions to adjust the median of the growth charts by sex and age, and suggest visual diagnostics to compare with the target population. We applied this workflow in a population of 1206 HIV-positive African children, consisting of 19 742 observations with weight ranging from 3.8 to 79.7 kg, height from 55.5 to 180 cm, and an age between 0.40 and 18 years. RESULTS: Before adjustment, the WHO and CDC charts produced weights and heights higher compared to the observed data. After applying our methodology, we could simulate weight, height, sex and age combinations in good agreement with the observed data. CONCLUSION: The methodology presented here is flexible and may be applied to other scenarios where WHO and CDC growth standards might not be appropriate. In addition we provide R scripts and a large ready-to-use paediatric population
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First Pharmacokinetic Data of Tenofovir Alafenamide Fumarate and Tenofovir With Dolutegravir or Boosted Protease Inhibitors in African Children: A Substudy of the CHAPAS-4 Trial.
BACKGROUND: We evaluated the pharmacokinetics of tenofovir alafenamide fumarate (TAF) and tenofovir in a subset of African children enrolled in the CHAPAS-4 trial. METHODS: Children aged 3-15 years with human immunodeficiency virus infection failing first-line antiretroviral therapy were randomized to emtricitabine/TAF versus standard-of-care nucleoside reverse transcriptase inhibitor combination, plus dolutegravir, atazanavir/ritonavir, darunavir/ritonavir, or lopinavir/ritonavir. Daily emtricitabine/TAF was dosed according to World Health Organization (WHO)-recommended weight bands: 120/15 mg in children weighing 14 to <25 kg and 200/25 mg in those weighing ≥25 kg. At steady state, 8-9 blood samples were taken to construct pharmacokinetic curves. Geometric mean (GM) area under the concentration-time curve (AUC) and the maximum concentration (Cmax) were calculated for TAF and tenofovir and compared to reference exposures in adults. RESULTS: Pharmacokinetic results from 104 children taking TAF were analyzed. GM (coefficient of variation [CV%]) TAF AUClast when combined with dolutegravir (n = 18), darunavir/ritonavir (n = 34), or lopinavir/ritonavir (n = 20) were 284.5 (79), 232.0 (61), and 210.2 (98) ng*hour/mL, respectively, and were comparable to adult reference values. When combined with atazanavir/ritonavir (n = 32), TAF AUClast increased to 511.4 (68) ng*hour/mL. For each combination, tenofovir GM (CV%) AUCtau and Cmax remained below reference values in adults taking 25 mg TAF with a boosted protease inhibitors. CONCLUSIONS: In children, TAF combined with boosted PIs or dolutegravir and dosed according to WHO-recommended weight bands provides TAF and tenofovir concentrations previously demonstrated to be well tolerated and effective in adults. These data provide the first evidence for use of these combinations in African children. CLINICAL TRIALS REGISTRATION: ISRCTN22964075
Constructing a representative in-silico population for pediatric simulations: application to HIV positive African children
Aims: Simulations are an essential tool for investigating scenarios in pharmacokinetics-pharmacodynamics. The models used during simulation often include the effect of highly correlated covariates such as weight, height, and sex and for children also age, which complicates the construction of an in-silico population. For this reason, a suitable and representative patient population is crucial for the simulations to produce meaningful results. For simulation in pediatric patients, international growth charts from the WHO and CDC provide a reference, but these may not always be representative for specific populations, such as malnourished children with HIV, or acutely unwell children.
Methods: We present a workflow to construct a virtual pediatric patient population using WHO and CDC growth charts, suggest piecewise linear functions to adjust the median of the growth charts by sex and age, and suggest visual diagnostics to compare with the target population. We applied this workflow in a population of 1,206 HIV-positive African children, consisting of 19,742 observations with weight ranging from 3.8 to 79.7 kg, height from 55.5 to 180 cm, and an age between 0.40 and 18 years.
Results: Before adjustment, the WHO and CDC charts produced weights and heights higher compared to the observed data. After applying our methodology, we could simulate weight, height, sex and age combinations in good agreement with the observed data.
Conclusion: The methodology presented here is flexible and may be applied to other scenarios where WHO and CDC growth standards might not be appropriate, in addition we provide R scripts and a large ready-to-use pediatric population.</p