1921
Volume 97, Issue 2
  • ISSN: 0002-9637
  • E-ISSN: 1476-1645

Abstract

Abstract.

Artemisinin-based combination therapies are recommended as first-line agents for treating uncomplicated 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 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 = 12 for each ferroquine dose and = 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 One ferroquine 100 mg + AS patient after one dose was withdrawn after developing a QTcF interval prolongation 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)

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2017-08-02
2018-11-15
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References

  1. Hawkes M, Conroy AL, Kain KC, , 2014. Spread of artemisinin resistance in malaria. N Engl J Med 371: 19441945.[Crossref]
  2. Biot C, Nosten F, Fraisse L, Ter-Minassian D, Khalife J, Dive D, , 2011. The antimalarial ferroquine: from bench to clinic. Parasite 18: 207214.[Crossref]
  3. Atteke C, Ndong JM, Aubouy A, , Maciejewski L, Brocard J, Lébibi J, Deloron P, 2003. In vitro susceptibility to a new antimalarial organometallic analogue, ferroquine, of Plasmodium falciparum isolates from the Haut-Ogooue region of Gabon. J Antimicrob Chemother 51: 10211024.[Crossref]
  4. Barends M, Jaidee A, Khaohirun N, Singhasivanon P, Nosten F, , 2007. In vitro activity of ferroquine (SSR 97193) against Plasmodium falciparum isolates from the Thai-Burmese border. Malar J 6: 81.[Crossref]
  5. Eyase FL, Akala HM, Johnson JD, Walsh DS, , 2011. Inhibitory activity of ferroquine, versus chloroquine, against western Kenya Plasmodium falciparum field isolates determined by a SYBR Green I in vitro assay. Am J Trop Med Hyg 85: 984988.[Crossref]
  6. Kreidenweiss A, Kremsner PG, Dietz K, Mordmuller B, , 2006. In vitro activity of ferroquine (SAR97193) is independent of chloroquine resistance in Plasmodium falciparum . Am J Trop Med Hyg 75: 11781181.
  7. Held J, Supan C, Salazar CL, , Tinto H, Bonkian LN, Nahum A, Moulero B, Sié A, Coulibaly B, Sirima SB, Siribie M, Otsyula N, Otieno L, Abdallah AM, Kimutai R, Bouyou-Akotet M, Kombila M, Koiwai K, Cantalloube C, Din-Bell C, Djeriou E, Waitumbi J, Mordmüller B, Ter-Minassian D, Lell B, Kremsner PG, 2015. Ferroquine and artesunate in African adults and children with Plasmodium falciparum malaria: a phase 2, multicentre, randomised, double-blind, dose-ranging, non-inferiority study. Lancet Infect Dis 15: 14091419.[Crossref]
  8. Wani WA, Jameel E, Baig U, Mumtazuddin S, Hun LT, , 2015. Ferroquine and its derivatives: new generation of antimalarial agents. Eur J Med Chem 101: 534551.[Crossref]
  9. Wells TN, Hooft van Huijsduijnen R, , 2015. Ferroquine: welcome to the next generation of antimalarials. Lancet Infect Dis 15: 13651366.[Crossref]
  10. Mombo-Ngoma G, Supan C, Dal-Bianco MP, , Missinou MA, Matsiegui PB, Ospina Salazar CL, Issifou S, Ter-Minassian D, Ramharter M, Kombila M, Kremsner PG, Lell B, 2011. Phase I randomized dose-ascending placebo-controlled trials of ferroquine—a candidate anti-malarial drug—in adults with asymptomatic Plasmodium falciparum infection. Malar J 10: 53.[Crossref]
  11. Supan C, Mombo-Ngoma G, Dal-Bianco MP, , Ospina Salazar CL, Issifou S, Mazuir F, Filali-Ansary A, Biot C, Ter-Minassian D, Ramharter M, Kremsner PG, Lell B, 2012. Pharmacokinetics of ferroquine, a novel 4-aminoquinoline, in asymptomatic carriers of Plasmodium falciparum infections. Antimicrob Agents Chemother 56: 31653173.[Crossref]
  12. Navarro VJ, Senior JR, , 2006. Drug-related hepatotoxicity. N Engl J Med 354: 731739.[Crossref]
  13. Common Toxicity Criteria for Adverse Events, version 4.0 (CTCAEv4): National Cancer Institute, National Institutes of Health, Bethesda, MD.
  14. Manning J, Vanachayangkul P, Lon C, , Spring M, So M, Sea D, Se Y, Somethy S, Phann ST, Chann S, Sriwichai S, Buathong N, Kuntawunginn W, Mitprasat M, Siripokasupkul R, Teja-Isavadharm P, Soh E, Timmermans A, Lanteri C, Kaewkungwal J, Auayporn M, Tang D, Chour CM, Prom S, Haigney M, Cantilena L, Saunders D, 2014. Randomized, double-blind, placebo-controlled clinical trial of a two-day regimen of dihydroartemisinin-piperaquine for malaria prevention halted for concern over prolonged corrected QT interval. Antimicrob Agents Chemother 58: 60566067.[Crossref]
  15. Atterhog JH, Malmberg P, , 1981. Prevalence of primary T-wave changes in young men and their relationship to psychological and anthropometric data. Clin Cardiol 4: 9197.[Crossref]
  16. Vandenberk B, Vandael E, Robyns T, , Vandenberghe J, Garweg C, Foulon V, Ector J, Willems R, 2016. Which QT correction formulae to use for QT monitoring? J Am Heart Assoc 5: pii: e003264.[Crossref]
  17. Moorman AC, Drobenuic J, Kamili S, , 2017. Prevalence of false-positive hepatitis C antibody results, National Health and Nutrition Examination Study (NHANES) 2007–2012. J Clin Virol 89: 14.[Crossref]
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Supplementary Data

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  • Received : 08 Sep 2016
  • Accepted : 06 Apr 2017

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