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Background <p>Treatment recommendations for malaria in infants of &lt; 5&#xa0;kg body weight (BW) are not evidence-based. Due to pharmacokinetic characteristics of this population, weight-based dose adjustments for antimalarials may be suboptimal. The 20&#xa0;mg artemether:120&#xa0;mg lumefantrine dispersible tablet, even with dose adjustment, may lead to artemether over-exposure and reduced lumefantrine exposure in patients &lt; 5&#xa0;kg. PBPK modelling predicted that a 1:12 artemether:lumefantrine ratio dispersible tablet should match efficacious and safe drug exposures in patients 5- &lt; 15&#xa0;kg treated with the current artemether–lumefantrine dispersible tablet: the CALINA study used an exposure-matching approach to confirm that drug exposures were comparable.</p> Methods <p>Sequential age cohorts (Cohort 1: &gt; 28&#xa0;days; Cohort 2: 1–28&#xa0;days) of patients &lt; 5&#xa0;kg with <i>Plasmodium falciparum</i> malaria received the new artemether–lumefantrine dispersible tablet (each dose 5&#xa0;mg artemether: 60&#xa0;mg lumefantrine) twice daily for 3&#xa0;days. Artemether C<sub>max</sub>, and lumefantrine C<sub>168h</sub> and C<sub>max</sub> were compared with historical data from patients 5– &lt; 15&#xa0;kg treated with the current artemether–lumefantrine dispersible tablet. The primary endpoint was met if the 90% CI for artemether C<sub>max</sub> contained the LS mean value from historical data (101&#xa0;ng/mL). PCR-corrected and uncorrected ACPR at Days 15, 29 and 43 and parasite clearance time were evaluated. Adverse events, laboratory evaluations, and developmental assessments were performed.</p> Results <p>In Cohort 1 (<i>N</i> = 22), geometric mean artemether C<sub>max</sub> was 68.0&#xa0;ng/mL (90% CI 45.1,103&#xa0;ng/mL); therefore, C<sub>max</sub> was comparable to that in historical data, meeting the primary endpoint. In Cohort 2 (<i>N</i> = 6), there were too few patients for formal analysis, but geometric mean artemether C<sub>max</sub> was comparable to that in Cohort 1 (62.2&#xa0;ng/mL, 90% CI 33.6,115&#xa0;ng/mL). In both cohorts, lumefantrine C<sub>168h</sub> and C<sub>max</sub> were comparable to historical data. PCR-corrected Day 29 ACPR was 95.5% and 100% in Cohorts 1 and 2, respectively. Treatment was well-tolerated. Developmental assessments at 12&#xa0;months of age were within the normal range.</p> Conclusions <p>The optimized dose of artemether–lumefantrine (5&#xa0;mg/60&#xa0;mg) achieves the exposures required for optimal efficacy and safety in patients &lt; 5&#xa0;kg body weight with <i>P. falciparum</i> malaria, consistent with those in patients 5– &lt; 15&#xa0;kg treated with the current dispersible tablet (20&#xa0;mg/120&#xa0;mg).</p> <p><i>Trial registry</i>: Clinicaltrials.gov: NCT04300309.</p>

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Pharmacokinetics, safety and efficacy of an optimized dose of artemether–lumefantrine in the treatment of acute uncomplicated Plasmodium falciparum malaria in neonates and infants of less than 5 kg body weight: a multicentre, open-label, single-arm phase 2/3 study (CALINA)

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  • 发表日期：

    2025年11月6日

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  • Gildas Wounounou,
  • Alfred B. Tiono,
  • Bernhards Ogutu,
  • Christine Manyando,
  • Issaka Sagara,
  • Stefan Schneitter,
  • Quique Bassat,
  • Myriam El Gaaloul,
  • Anne Claire Marrast,
  • Ivan Demin,
  • Cornelis Winnips,
  • Celine Risterucci,
  • Sophie Hugot,
  • Georg Hofstetter,
  • Zhiyan Qian,
  • Guoqin Su,
  • Jie Zhang,
  • Katalin Csermak Renner,
  • Marc Cousin,
  • Vinay Kumar Venishetty,
  • Sarfaraz Sayyed,
  • Preetam Gandhi,
  • Berenger Kabore

摘要

Background

Treatment recommendations for malaria in infants of < 5 kg body weight (BW) are not evidence-based. Due to pharmacokinetic characteristics of this population, weight-based dose adjustments for antimalarials may be suboptimal. The 20 mg artemether:120 mg lumefantrine dispersible tablet, even with dose adjustment, may lead to artemether over-exposure and reduced lumefantrine exposure in patients < 5 kg. PBPK modelling predicted that a 1:12 artemether:lumefantrine ratio dispersible tablet should match efficacious and safe drug exposures in patients 5- < 15 kg treated with the current artemether–lumefantrine dispersible tablet: the CALINA study used an exposure-matching approach to confirm that drug exposures were comparable.

Methods

Sequential age cohorts (Cohort 1: > 28 days; Cohort 2: 1–28 days) of patients < 5 kg with Plasmodium falciparum malaria received the new artemether–lumefantrine dispersible tablet (each dose 5 mg artemether: 60 mg lumefantrine) twice daily for 3 days. Artemether Cmax, and lumefantrine C168h and Cmax were compared with historical data from patients 5– < 15 kg treated with the current artemether–lumefantrine dispersible tablet. The primary endpoint was met if the 90% CI for artemether Cmax contained the LS mean value from historical data (101 ng/mL). PCR-corrected and uncorrected ACPR at Days 15, 29 and 43 and parasite clearance time were evaluated. Adverse events, laboratory evaluations, and developmental assessments were performed.

Results

In Cohort 1 (N = 22), geometric mean artemether Cmax was 68.0 ng/mL (90% CI 45.1,103 ng/mL); therefore, Cmax was comparable to that in historical data, meeting the primary endpoint. In Cohort 2 (N = 6), there were too few patients for formal analysis, but geometric mean artemether Cmax was comparable to that in Cohort 1 (62.2 ng/mL, 90% CI 33.6,115 ng/mL). In both cohorts, lumefantrine C168h and Cmax were comparable to historical data. PCR-corrected Day 29 ACPR was 95.5% and 100% in Cohorts 1 and 2, respectively. Treatment was well-tolerated. Developmental assessments at 12 months of age were within the normal range.

Conclusions

The optimized dose of artemether–lumefantrine (5 mg/60 mg) achieves the exposures required for optimal efficacy and safety in patients < 5 kg body weight with P. falciparum malaria, consistent with those in patients 5– < 15 kg treated with the current dispersible tablet (20 mg/120 mg).

Trial registry: Clinicaltrials.gov: NCT04300309.