Atovaquone + Proguanil - Drug Interactions

Clinical evidence,mechanism, importance and management

Atovaquone did not affect pharmacokinetics of proguanil in a comparative study of 4 patients taking proguanil 200mg twice daily for 3 days and 12 patients taking proguanil 200mg twice daily with atovaquone 500mg twice daily for 3 days (See reference number 1)

In contrast,in a longer study 13 healthy subjects were given a single 250/100-mg dose of atovaquone/proguanil, then after an interval of one week they were given daily doses for 13 days. There was no change in AUC of atovaquone from single dose to steady state, indicating that accumulation did not occur. However, AUC of proguanil was modestly increased at steady state, and AUC of active metabolite cycloguanil was modestly decreased, in 9 subjects who were extensive metaboliser phenotypes for cytochrome P450 isoenzyme CYP2C19 (see Genetic factors, ). It was suggested that atovaquone may have inhibited production of cycloguanil by CYP3A4. However,since this study had no arm with each drug alone, it is impossible to determine whether these changes in pharmacokinetics were due to an interaction or not (See reference number 3).

A pharmacokinetic interaction is not established, and is anyway of little clinical relevance, since efficacy of combination product for malaria prophylaxis up to 12 weeks is established. The enhanced activity of combination may, in part, be due to proguanil lowering effective concentration at which atovaquone collapses mitochondrial potential in malaria parasites (See reference number 4).

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Gillotin C,Mamet JP, Veronese L. Lack of pharmacokinetic interaction between atovaquoneand proguanil. Eur J Clin Pharmacol (1999) 55, 311–15.

Thapar MM,Ashton M, Lindegardh N, Bergqvist Y, Nivelius S, Johansson I, Bjorkman A.Time-dependent pharmacokinetics and drug metabolism of atovaquone plus proguanil (Malarone) when taken as chemoprophylaxis. Eur J Clin Pharmacol (2002) 58, 19–27.

Srivastava IK,Vaidya AB. A mechanism for the synergistic antimalarial action of atovaquoneand proguanil. Antimicrob Agents Chemother (1999) 43, 1334–9.