title: Minocycline as a re-purposed anti-Wolbachia macrofilaricide: superiority compared with doxycycline regimens in a murine infection model of human lymphatic filariasis.
abstract: Lymphatic filariasis and onchocerciasis are parasitic helminth diseases, which cause severe morbidities such as elephantiasis, skin disease and blindness, presenting a major public health burden in endemic communities. The anti-Wolbachia consortium (A·WOL: http://www.a-wol.com/) has identified a number of registered antibiotics that target the endosymbiotic bacterium, Wolbachia, delivering macrofilaricidal activity. Here we use pharmacokinetics/pharmacodynamics (PK/PD) analysis to rationally develop an anti-Wolbachia chemotherapy by linking drug exposure to pharmacological effect. We compare the pharmacokinetics and anti-Wolbachia efficacy in a murine Brugia malayi model of minocycline versus doxycycline. Doxycycline exhibits superior PK in comparison to minocycline resulting in a 3-fold greater exposure in SCID mice. Monte-Carlo simulations confirmed that a bi-daily 25-40 mg/Kg regimen is bioequivalent to a clinically effective 100-200 mg/day dose for these tetracyclines. Pharmacodynamic studies showed that minocycline depletes Wolbachia more effectively than doxycycline (99.51% vs. 90.35%) after 28 day 25 mg/Kg bid regimens with a more potent block in microfilarial production. PK/PD analysis predicts that minocycline would be expected to be 1.7 fold more effective than doxycycline in man despite lower exposure in our infection models. Our findings warrant onward clinical investigations to examine the clinical efficacy of minocycline treatment regimens against lymphatic filariasis and onchocerciasis.
authors.affiliation: Department of Parasitology, Liverpool School of Tropical Medicine, Pembroke Place, Liverpool L3 5QA, UK.
authors.forename: Raman
authors.initials: R
authors.lastname: Sharma
authors.affiliation: Department of Parasitology, Liverpool School of Tropical Medicine, Pembroke Place, Liverpool L3 5QA, UK.
authors.forename: Ghaith
authors.initials: G
authors.lastname: Al Jayoussi
authors.affiliation: Department of Parasitology, Liverpool School of Tropical Medicine, Pembroke Place, Liverpool L3 5QA, UK.
authors.forename: Hayley E
authors.initials: HE
authors.lastname: Tyrer
authors.affiliation: Department of Parasitology, Liverpool School of Tropical Medicine, Pembroke Place, Liverpool L3 5QA, UK.
authors.forename: Joanne
authors.initials: J
authors.lastname: Gamble
authors.affiliation: Department of Parasitology, Liverpool School of Tropical Medicine, Pembroke Place, Liverpool L3 5QA, UK.
authors.forename: Laura
authors.initials: L
authors.lastname: Hayward
authors.affiliation: Department of Parasitology, Liverpool School of Tropical Medicine, Pembroke Place, Liverpool L3 5QA, UK.
authors.forename: Ana F
authors.initials: AF
authors.lastname: Guimaraes
authors.affiliation: Department of Parasitology, Liverpool School of Tropical Medicine, Pembroke Place, Liverpool L3 5QA, UK.
authors.forename: Jill
authors.initials: J
authors.lastname: Davies
authors.affiliation: Department of Parasitology, Liverpool School of Tropical Medicine, Pembroke Place, Liverpool L3 5QA, UK.
authors.forename: David
authors.initials: D
authors.lastname: Waterhouse
authors.affiliation: Department of Parasitology, Liverpool School of Tropical Medicine, Pembroke Place, Liverpool L3 5QA, UK.
authors.forename: Darren A N
authors.initials: DA
authors.lastname: Cook
authors.affiliation: Department of Parasitology, Liverpool School of Tropical Medicine, Pembroke Place, Liverpool L3 5QA, UK.
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Myhill
authors.affiliation: Department of Parasitology, Liverpool School of Tropical Medicine, Pembroke Place, Liverpool L3 5QA, UK.
authors.forename: Rachel H
authors.initials: RH
authors.lastname: Clare
authors.affiliation: Department of Parasitology, Liverpool School of Tropical Medicine, Pembroke Place, Liverpool L3 5QA, UK.
authors.forename: Andrew
authors.initials: A
authors.lastname: Cassidy
authors.affiliation: Department of Parasitology, Liverpool School of Tropical Medicine, Pembroke Place, Liverpool L3 5QA, UK.
authors.forename: Andrew
authors.initials: A
authors.lastname: Steven
authors.affiliation: Department of Parasitology, Liverpool School of Tropical Medicine, Pembroke Place, Liverpool L3 5QA, UK.
authors.forename: Kelly L
authors.initials: KL
authors.lastname: Johnston
authors.affiliation: Department of Parasitology, Liverpool School of Tropical Medicine, Pembroke Place, Liverpool L3 5QA, UK.
authors.forename: Louise
authors.initials: L
authors.lastname: Ford
authors.affiliation: Department of Parasitology, Liverpool School of Tropical Medicine, Pembroke Place, Liverpool L3 5QA, UK.
authors.forename: Joseph D
authors.initials: JD
authors.lastname: Turner
authors.affiliation: Department of Parasitology, Liverpool School of Tropical Medicine, Pembroke Place, Liverpool L3 5QA, UK.
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Ward
authors.affiliation: Department of Parasitology, Liverpool School of Tropical Medicine, Pembroke Place, Liverpool L3 5QA, UK.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Taylor
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D017178:Brugia malayi / Q000187:drug effects / Q000469:parasitology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004318:Doxycycline / Q000008:administration & dosage / Q000493:pharmacokinetics; D004605:Elephantiasis, Filarial / Q000469:parasitology / Q000517:prevention & control*; D005260:Female; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D008911:Minocycline / Q000008:administration & dosage* / Q000493:pharmacokinetics; D020577:Wolbachia / Q000187:drug effects* / Q000472:pathogenicity
chemical_list: D000900:Anti-Bacterial Agents; D008911:Minocycline; D004318:Doxycycline