Mechanism of Action: Sulfadoxine and pyrimethamine, the constituents of Fansidar, are folic acid antagonists. Sulfadoxine inhibits the activity of dihydropteroate synthase whereas pyrimethamine inhibits dihydrofolate reductase.

Activity in vitro: Sulfadoxine and pyrimethamine are active against the asexual erythrocytic stages of Plasmodium falciparum. Fansidar may also be effective against strains of P. falciparum resistant to chloroquine.

Drug Resistance: Strains of P. falciparum with decreased susceptibility to sulfadoxine and /or pyrimethamine can be selected in vitro or in vivo. P. falciparum malaria that is clinically resistant to Fansidar occurs frequently in parts of Southeast Asia and South America, and is also prevalent in East and Central Africa. Therefore, Fansidar should be used with caution in these areas. Likewise, Fansidar may not be effective for treatment of recrudescent malaria that develops after prior therapy (or prophylaxis) with Fansidar.

After administration of 1 tablet, peak plasma levels for pyrimethamine (approximately 0.2 mg/L) and for sulfadoxine (approximately 60 mg/L) are reached after about 4 hours.

The volume of distribution for sulfadoxine and pyrimethamine is 0.14 L/kg and 2.3 L/kg, respectively. Patients taking 1 tablet a week (recommended adult dose for malaria prophylaxis) can be expected to have mean steady state plasma concentrations of about 0.15 mg/L for pyrimethamine after about four weeks and about 98 mg/L for sulfadoxine after about seven weeks. Plasma protein binding is about 90% for both pyrimethamine and sulfadoxine. Both pyrimethamine and sulfadoxine cross the placental barrier and pass into breast milk.

About 5% of sulfadoxine appears in the plasma as acetylated metabolite, about 2 to 3% as the glucuronide. Pyrimethamine is transformed to several unidentified metabolites.

A relatively long elimination half-life is characteristic of both components. The mean values are about 100 hours for pyrimethamine and about 200 hours for sulfadoxine. Both pyrimethamine and sulfadoxine are eliminated mainly via the kidneys.

In malaria patients, single pharmacokinetic parameters may differ from those in healthy subjects, depending on the population concerned. In patients with renal insufficiency, delayed elimination of the components of Fansidar must be anticipated.

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