Pharmacokinetics and dynamics of atovaquone and proguanil (Malarone®)

Malarone® is a fixed dose combination of atovaquone and proguanil and is mainly used for prophylaxis against P. falciparum malaria as an alternative to Lariamo® or chloroquine+proguanil. Knowledge of pharmacokinetics (PK) and pharmacodynamics (PD) is required to describe, quantify, and predict drug effects in humans in order to achieve desired therapeutic activity with minimum side effects. PK and PD of Malarone® were therefore studied with the aim to contribute to a better understanding of interactions among atovaquone, proguanil and cycloguanil and/or with other coadministered drugs.

Our data suggest that PK of proguanil and cycloguanil are altered after multiple doses of Malarone® and PK of atovaquone are altered after concomitant administration with ketoconazole or rifampicin. Atovaquone appears to alter the PK of proguanil and cycloguanil at steady state after multiple daily doses of Malarone® in healthy individuals. In vitro enzyme kinetics experiments suggest inhibition of catalytic activity of CYP3A4 by atovaquone. Ketoconazole, an inhibitor of CYP3A4 and membrane transport proteins, significantly increased the oral bioavailability of atovaquone, upon coadministration with Malarone®. In contrast, rifampicin, an inducer of CYP3A4 and membrane transport proteins, increased clearance of atovaquone. The alteration in PK may indirectly suggest involvement of CYP3A4 in metabolism and/or transport proteins in active uptake and/or efflux of atovaquone.

In vitro, at clinically relevant drug concentrations and combination ratios, atovaquone and proguanil exhibit synergistic PD interactions against P. falciparum parasites in vitro. Furthermore, low concentrations of proguanil, approximately equivalent to 0.2 times its EC90 value, are sufficient to enhance the effect of atovaquone. In contrast to this, interactions between atovaquone and cycloguanil were mainly antagonistic. Hence, the reduced cycloguanil concentrations after multiple doses of Malarone® will not be detrimental to its efficacy. Some P. falciparum parasites, exposed to various concentrations of atovaquone with or without proguanil, seem to adopt a 'dormant state' and survive for up to 24 days in cultures. These parasites show no genetic alterations thereby suggesting some other mechanism of escape from the drug effects.

We report Malarone® treatment failures in two patients with P. falciparum malaria. Molecular analysis of parasitic DNA revealed mutations in cytochrome b gene (cytb) in one case but wild type alleles in the other. Also, the presence of mutant alleles in a third patient, who was cured, suggests that genetic mutations in cyth may be correlated but they are neither necessary nor sufficient condition to produce Malarone® resistance in vivo.

In conclusion, high efficacy of Malarone® relies on synergistic interaction between atovaquone and proguanil and thus does not depend upon metabolism of proguanil to cycloguanil. Atovaquone seems to be a substrate for one or more membrane transport proteins. Thus, travelers on Malarone® prophylaxis, who may be taking other medications, may be predisposed to increased risk of drug-drug interactions. The presence of 'dormant state' parasites during exposure to atovaquone/proguanil suggests that factors other than cytb alterations may be involved as mechanisms of resistance to Malarone®.

List of scientific papers

I. Thapar MM, Ashton M, Lindegardh N, Bergqvist Y, Nivelius S, Johansson I, Bjorkman A (2002). "Time-dependent pharmacokinetics and drug metabolism of atovaquone plus proguanil (Malarone) when taken as chemoprophylaxis." Eur J Clin Pharmacol 58(1): 19-27. Epub 2002 Feb 28
https://pubmed.ncbi.nlm.nih.gov/11956669

II. Thapar MM, Gil JP, Ashton M, Ursing J, Lindkvist J, Bergqvist Y, Bjorkman A (2004). "Ketoconazole and rifampicin alter the pharmacokinetics of atovaquone in healthy subjects." (Manuscript)

III. Thapar MM, Gupta S, Spindler C, Wernsdorfer WH, Bjorkman A (2003). "Pharmacodynamic interactions among atovaquone, proguanil and cycloguanil against Plasmodium falciparum in vitro. " Trans R Soc Trop Med Hyg 97(3): 331-7
https://pubmed.ncbi.nlm.nih.gov/15228254

IV. Farnert A, Lindberg J, Gil P, Swedberg G, Berqvist Y, Thapar MM, Lindegardh N, Berezcky S, Bjorkman A (2003). "Evidence of Plasmodium falciparum malaria resistant to atovaquone and proguanil hydrochloride: case reports. " BMJ 326(7390): 628-9
https://pubmed.ncbi.nlm.nih.gov/12649236

V. Thapar MM, Gil JP, Bjorkman A (2004). "In vitro recrudescence of P.falciparum parasites suppresed to dormant state by atovaquone alone and in combination with proguanil." Transactions of the Royal Society of Tropical Medicine and Hygiene 98: (In Print)