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PERSISTENCE OF ATOVAQUONE IN HUMAN SERA FOLLOWING TREATMENT: INHIBITION OF P. FALCIPARUM DEVELOPMENT IN VIVO AND IN VITRO

Published pharmacokinetic data indicate that after treatment of patients with therapeutic doses of atovaquone/proguanil hydrochloride (Malarone^TM, GlaxoSmithKline Research Triangle Park, NC), the plasma half-lives of these drugs are 70h and 15h, respectively. However, using two biologic assays (mosquito transmission and in vitro asexual stage development), we demonstrate here that sera from volunteers treated with atovaquone/proguanil retained activity against Plasmodium falciparum up to 6 weeks after such treatment. This activity was due to atovaquone, as administration of this drug alone replicated the data obtained with the combination. Most notably, asexual stage development of an atovaquone-resistant strain (NGATV01) of P. falciparum was not inhibited by sera taken after atovaquone treatment. These data indicate that for atovaquone, biologic assays, though not quantitative, are more sensitive than the usual physicochemical assays. Also, persistence of atovaquone in plasma at low concentrations for long periods may increase the risk of resistant parasites arising.

Received April 17, 2002. Accepted for publication August 22, 2002.

Acknowledgments: We thank GlaxoWellcome (now GlaxoSmith-Kline) for the supply of Malarone and atovaquone. We also thank our volunteers who took the drugs and donated sera, and J. Mendoza for keeping us supplied with mosquitoes.

Financial support: Dr. Butcher was supported by GlaxoWellcome (now GlaxoSmithKline).

Reprint requests: Dr. G. Butcher, Department of Biologic Sciences, Imperial College of Science Technology and Medicine, Sir Alexander Fleming Building, Imperial College Road, London SW7 2AZ UK, Telephone: 44-0207-5945381, Fax: 44-0207-5495425, E-mail: g.butcher{at}ic.ac.uk

Authors’ addresses: Dr. G. Butcher, Prof. RE Sinden, Department of Biologic Sciences, Imperial College of Science Technology and Medicine, Sir Alexander Fleming Building, Imperial College Road, London.

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