High-Dose Chloroquine for Uncomplicated Plasmodium falciparum Malaria Is Well Tolerated and Causes Similar QT Interval Prolongation as Standard-Dose Chloroquine in Children

Abstract

Higher chloroquine doses can effectively treat up to 93 to 96% of malaria infections caused by Plasmodium falciparum carrying the resistance-conferring chloroquine resistance transporter (pfcrt) 76T allele. The tolerability of 50 (double the standard dose) and 70 mg/kg total chloroquine doses were assessed in this study. Fifteen 4- to 8-year-old children with uncomplicated malaria were given 10 mg/kg of chloroquine twice daily for 2 days and 5 mg/kg twice daily on the third day. Fifteen additional children were given 5 mg/kg twice daily for 2 more days. Chloroquine concentrations, blood pressure, electrocardiograms (ECGs), parasite density, and adverse events were assessed until day 28. Both dosages were well tolerated, and symptoms resolved by day 3 in parallel with increasing chloroquine concentrations. The median corrected QT (QTc) interval was 12 to 26 ms higher at expected peak concentrations than at day 0 (P < 0.001). Pfcrt 76T was associated with delayed parasite clearance. Day 28 clinical and parasitological responses against P. falciparum with pfcrt 76T were 57% (4/7) and 67% (4/6) after treatment with 50 and 70 mg/kg, respectively. Dosages were well tolerated, and no severe cardiac adverse events occurred. The QTc interval increase was similar to that found in adults taking 25 mg/kg of chloroquine. (This study has been registered at ClinicalTrials.gov under identifier NCT01814423.).

Keywords: Guinea-Bissau; Plasmodium falciparum; cardiac safety; chloroquine; pfcrt; pharmacokinetics; tolerability; treatment.

FIG 1

Symptom resolution during treatment with 50 and 70 mg/kg of chloroquine. (A) Feeling unwell, feverish, or having joint pains or headache. (B) Vomiting, diarrhea, or stomach pain. (C) Sleeping, eating, and drinking, White, no symptoms; stripes, moderate symptoms; black, severe symptoms.

FIG 2

Cardiac repolarization time, chloroquine concentrations, and pulse rates before, during, and after treatment. The open and black circles represent the 50 mg/kg and 70 mg/kg total chloroquine doses, respectively.

FIG 3

Parasite and fever clearance. (A) Median and interquartile range parasite density with the pfcrt K76T allele. (B) Proportion of children with P. falciparum parasitemia with the pfcrt K76T allele. (C) Median temperature and interquartile range. Black and open circles represent the chloroquine-sensitive pfcrt K76 and chloroquine-resistant pfcrt 76T alleles, respectively, in panels A and B.