Cethromycin Pharmacokinetics and Pharmacodynamics for Single Dose Cure of Plasmodium berghei Liver Stages
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Abstract
Cethromycin combines a quinoline nucleus and a macrolide for broad spectrum antibacterial and antiprotozoan activity. Here we characterized the murine pharmacokinetics and Plasmodium berghei lifecycle stage pharmacodynamics for the cethromycin base. Liver pharmacokinetic studies in mice show peak mM drug levels in the liver with 20 hour sustained levels above 10 μM. Peak concentrations in the liver were double the lung and about 440 times that of plasma. Immunofluorescence imaging of in vitro cethromycin-treated infected hepatocytes shows complete ablation of the apicoplast. We observed complete cure of P. berghei liver stage infection by single oral dose of 60 mg/kg in mice which is equivalent to the 5 mg/kg human dose of 300 mg a day used in bacterial pneumonia studies. Cethromycin at 60 mg/kg daily for 7 days was curative in the high parasitemic P. berghei mouse model. Both mosquito membrane feeding of P. falciparum gametocytes incubated with 20 μM cethromycin and oral dosing in mice demonstrated no decrease in oocyst numbers. Cethromycin has been evaluated for efficacy against bacterial pneumonia in more than 5,000 patients with good safety profiles. Cethromycin has potential for rapid clinical development for casual malaria prophylaxis and possibly radical cure of dormant liver P. vivax .
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Abstract
Cethromycin combines a quinoline nucleus and a macrolide for broad spectrum antibacterial and antiprotozoan activity. Here we characterized the murine pharmacokinetics and Plasmodium berghei lifecycle stage pharmacodynamics for the cethromycin base. Liver pharmacokinetic studies in mice show peak mM drug levels in the liver with 20 hour sustained levels above 10 μM. Peak concentrations in the liver were double the lung and about 440 times that of plasma. Immunofluorescence imaging of in vitro cethromycin-treated infected hepatocytes shows complete ablation of the apicoplast. We observed complete cure of P. berghei liver stage infection by single oral dose of 60 mg/kg in mice which is equivalent to the 5 mg/kg human dose of 300 mg a day used in bacterial pneumonia studies. Cethromycin at 60 mg/kg daily for 7 days was curative in the high parasitemic P. berghei mouse model. Both mosquito membrane feeding of P. falciparum gametocytes incubated with 20 μM cethromycin and oral dosing in mice demonstrated no decrease in oocyst numbers. Cethromycin has been evaluated for efficacy against bacterial pneumonia in more than 5,000 patients with good safety profiles. Cethromycin has potential for rapid clinical development for casual malaria prophylaxis and possibly radical cure of dormant liver P. vivax.
Competing Interest Statement
DS is Founder, Board Member, and stock/option owner of AliquantumRx(macrolide for antimicrobial and malaria use); coinventor on USP 7,270,948 (Detection of malaria parasites by laser desorption mass spectrometry), USP9,568,471 (Malaria diagnosis in urine), USP 9,642,865 (New angiogenesis inhibitors), and PCT/US2015/046665 (Salts and polymorphs of cethromycin for the treatment of disease); and has received royalties from Binax Inc/D/B/A Inverness Medical for plasmids for HRP aldolase for malaria diagnostic kit. All other authors declare no competing interests. NK is Founder, Board Member, and stock/option owner of AliquantumRx(macrolide for antimicrobial and malaria use) and coinventor PCT/US2015/046665 (Salts and polymorphs of cethromycin for the treatment of disease). Other authors have no competing interests to declare.
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