Scholarlink

Background <p>Evidence-based recommendations for malaria treatment in patients weighing &lt; 5&#xa0;kg are lacking as a consequence of differences in pharmacokinetics due to age and/or body weight (BW), and recruitment challenges in conducting trials in this population. A physiologically based pharmacokinetic (PBPK) model was developed and validated to predict artemether and lumefantrine concentrations in patients &lt; 5&#xa0;kg BW aged 1–28&#xa0;days. The model predictions supplemented data from a trial (CALINA; NCT04300309) with an optimized dose of artemether–lumefantrine (5&#xa0;mg artemether: 60&#xa0;mg lumefantrine) in patients &lt; 5&#xa0;kg with <i>Plasmodium falciparum</i> malaria.</p> Methods <p>PBPK models of artemether and lumefantrine were developed using Simcyp (Version 22) and validation was performed using historical data from adults and paediatric patients. To compare model-predicted and observed values, populations were matched to clinical trial populations (ranging from adults to infants) for patient numbers and demographics. The models were applied to predict artemether maximal concentration (C<sub>max</sub>) and lumefantrine C<sub>max</sub> and Day 7 concentration (C<sub>168h</sub>) in neonates of &lt; 5&#xa0;kg BW aged 1–28&#xa0;days, and for subgroups aged 1–7, 8–14, and 15–28&#xa0;days.</p> Results <p>Validated models for artemether and lumefantrine were used to predict plasma concentrations in neonates and young infants with BW &lt; 5&#xa0;kg after 3-day administration of 5&#xa0;mg artemether and 60&#xa0;mg lumefantrine twice daily with high confidence. The PBPK model using Upreti hepatic cytochrome P450 (CYP)3A4 ontogeny predicted observed artemether and lumefantrine exposure in infants and neonates better than Salem ontogeny. The predicted variability in neonates was comparable to or larger than the variability of observed concentrations in infants and older neonates in the CALINA study.</p> Conclusions <p>Based on the success of the PBPK models for artemether and lumefantrine in predicting drug concentrations in adults and children, including neonates, modelling and simulation results can be used with confidence to supplement the limited available data for neonates (1–28&#xa0;days old) &lt; 5&#xa0;kg BW obtained from the CALINA study for this rarer and more difficult to recruit patient population.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Physiologically based pharmacokinetic modelling to predict artemether and lumefantrine exposure in neonates weighing less than 5 kg treated with artemether–lumefantrine to supplement the clinical data from the CALINA study

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年8月25日

查看全文
  • Helen Gu,
  • Nada Abla,
  • Vinay Kumar Venishetty,
  • Birgit Schoeberl,
  • Julia Zack,
  • Heidi J. Einolf

摘要

Background

Evidence-based recommendations for malaria treatment in patients weighing < 5 kg are lacking as a consequence of differences in pharmacokinetics due to age and/or body weight (BW), and recruitment challenges in conducting trials in this population. A physiologically based pharmacokinetic (PBPK) model was developed and validated to predict artemether and lumefantrine concentrations in patients < 5 kg BW aged 1–28 days. The model predictions supplemented data from a trial (CALINA; NCT04300309) with an optimized dose of artemether–lumefantrine (5 mg artemether: 60 mg lumefantrine) in patients < 5 kg with Plasmodium falciparum malaria.

Methods

PBPK models of artemether and lumefantrine were developed using Simcyp (Version 22) and validation was performed using historical data from adults and paediatric patients. To compare model-predicted and observed values, populations were matched to clinical trial populations (ranging from adults to infants) for patient numbers and demographics. The models were applied to predict artemether maximal concentration (Cmax) and lumefantrine Cmax and Day 7 concentration (C168h) in neonates of < 5 kg BW aged 1–28 days, and for subgroups aged 1–7, 8–14, and 15–28 days.

Results

Validated models for artemether and lumefantrine were used to predict plasma concentrations in neonates and young infants with BW < 5 kg after 3-day administration of 5 mg artemether and 60 mg lumefantrine twice daily with high confidence. The PBPK model using Upreti hepatic cytochrome P450 (CYP)3A4 ontogeny predicted observed artemether and lumefantrine exposure in infants and neonates better than Salem ontogeny. The predicted variability in neonates was comparable to or larger than the variability of observed concentrations in infants and older neonates in the CALINA study.

Conclusions

Based on the success of the PBPK models for artemether and lumefantrine in predicting drug concentrations in adults and children, including neonates, modelling and simulation results can be used with confidence to supplement the limited available data for neonates (1–28 days old) < 5 kg BW obtained from the CALINA study for this rarer and more difficult to recruit patient population.