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).

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.