Artemisinin-based combination
therapies are recommended as first-line agents for treating uncomplicated
Plasmodium falciparum malaria.
Ferroquine, a 4-aminoquinolone, is a novel long-acting combination partner for fast-acting drugs like
artesunate (AS). We did a small phase 2a, multicenter, open-label, safety-focused dose-ranging randomized study of
ferroquine at three African hospitals: two Gabonese and one Kenyan. We recruited adult men with symptomatic uncomplicated P. falciparum monoinfection. Four escalating doses of
ferroquine (100, 200, 400, and 600 mg) were assessed in sequence, versus an
amodiaquine comparator. After a 2:1 randomization (block size three, equating to N = 12 for each
ferroquine dose and N = 6 for each of four
amodiaquine comparator groups) patients received daily for three consecutive days, either
ferroquine + AS (200 mg/day) or
amodiaquine (612 mg/day) + AS (200 mg/day). Safety, electrocardiograms, parasite clearance times, efficacy, and pharmacokinetics were assessed to day 28. Seventy-two patients were randomized.
Ferroquine + AS showed generally mild increases (Grade 1 toxicity) in
alanine aminotransferase (ALT) levels with a dose trend starting at 400 mg. There were two Grade 2 ALT events: one patient receiving 200 mg (3.8 upper limit of normal [ULN], day 7) and one receiving 600 mg (3.3 ULN, day 14), both without increased
bilirubin. One
ferroquine 100 mg + AS patient after one dose was withdrawn after developing a QTcF interval prolongation > 60 milliseconds over baseline.
Parasitemias in all patients cleared quickly, with no recurrence through day 28. Hepatic, as well as cardiac, profiles should be monitored closely in future trials. (ClinicalTrials.gov: NCT00563914).