Long-acting injectable atovaquone nanomedicines for malaria prophylaxis

Rahul P Bakshi; Lee M Tatham; Alison C Savage; Abhai K Tripathi; Godfree Mlambo; Matthew M Ippolito; Elizabeth Nenortas; Steve P Rannard; Andrew Owen; Theresa A Shapiro

doi:10.1038/s41467-017-02603-z

Long-acting injectable atovaquone nanomedicines for malaria prophylaxis

Nat Commun. 2018 Jan 22;9(1):315. doi: 10.1038/s41467-017-02603-z.

Authors

Rahul P Bakshi^{1

2}, Lee M Tatham³, Alison C Savage⁴, Abhai K Tripathi^{2

5}, Godfree Mlambo^{2

5}, Matthew M Ippolito^{1

2

6}, Elizabeth Nenortas^{1

2}, Steve P Rannard⁷, Andrew Owen⁸, Theresa A Shapiro^{1

2

5}

Affiliations

¹ Division of Clinical Pharmacology, Departments of Medicine and of Pharmacology and Molecular Sciences, The Johns Hopkins University, 725 North Wolfe Street, Baltimore, MD, 21205, USA.
² The Johns Hopkins Malaria Research Institute, Baltimore, MD, 21205, USA.
³ Department of Molecular and Clinical Pharmacology, University of Liverpool, Block H, 70 Pembroke Place, Liverpool, L69 3GF, UK.
⁴ Department of Chemistry, University of Liverpool, Crown Street, Liverpool, L69 7ZD, UK.
⁵ Department of Molecular Microbiology and Immunology, The Johns Hopkins University, Baltimore, MD, 21205, USA.
⁶ Division of Infectious Diseases, Department of Medicine, The Johns Hopkins University, Baltimore, MD, 21205, USA.
⁷ Department of Chemistry, University of Liverpool, Crown Street, Liverpool, L69 7ZD, UK. srannard@liverpool.ac.uk.
⁸ Department of Molecular and Clinical Pharmacology, University of Liverpool, Block H, 70 Pembroke Place, Liverpool, L69 3GF, UK. aowen@liverpool.ac.uk.

Abstract

Chemoprophylaxis is currently the best available prevention from malaria, but its efficacy is compromised by non-adherence to medication. Here we develop a long-acting injectable formulation of atovaquone solid drug nanoparticles that confers long-lived prophylaxis against Plasmodium berghei ANKA malaria in C57BL/6 mice. Protection is obtained at plasma concentrations above 200 ng ml^-1 and is causal, attributable to drug activity against liver stage parasites. Parasites that appear after subtherapeutic doses remain atovaquone-sensitive. Pharmacokinetic-pharmacodynamic analysis indicates protection can translate to humans at clinically achievable and safe drug concentrations, potentially offering protection for at least 1 month after a single administration. These findings support the use of long-acting injectable formulations as a new approach for malaria prophylaxis in travellers and for malaria control in the field.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Anopheles / parasitology
Antimalarials / therapeutic use*
Atovaquone / blood*
Atovaquone / therapeutic use*
Chemoprevention / methods
Disease Models, Animal
Drug Carriers / therapeutic use*
Drug Resistance / genetics
Female
Humans
Malaria / drug therapy*
Malaria / prevention & control*
Male
Mice
Mice, Inbred C57BL
Nanoparticles / therapeutic use
Plasmodium berghei / drug effects*
Theranostic Nanomedicine

Substances

Antimalarials
Drug Carriers
Atovaquone

Abstract

Publication types

MeSH terms

Substances

Grants and funding