Clinical Pharmacokinetics of Anthelmintic Drugs

Summary

A rational strategy for chemotherapy demands that dosage schedules be based on an adequate knowledge of clinical and biochemical pharmacology. Many anthelmintic drugs (e.g. suramin, diethylcarbamazine, hycanthone) were introduced before modern techniques for drug evaluation (controlled clinical trials) and before the development of specific and sensitive analytical methods for the assay of drugs and metabolites in biological fluids. Thus, many of the regimens used today for the treatment of parasitic diseases are largely empirically derived. By means of specific analytical methodology (high performance liquid chromatography, gas chromatography and mass-spectrometry) introduced in the 1960s, it is now possible to measure drugs and their metabolites with specificity and sensitivity.

Much of this review deals with compounds which are active against the major systemic helminths, i.e., filariae (diethylcarbamazine, ivermectin and suramin) and schistosomes (niridazole, metrifonate, oxamniquine and praziquantel), but recent advances in the treatment of hydatid disease involving the benzimidazole carbamates albendazole and mebendazole are also discussed.

Among the imidazole derivatives, mebendazole, a broad-spectrum anthelmintic, is poorly absorbed from the gastrointestinal tract after a therapeutic dose, but that fraction which is absorbed and escapes hepatic first-pass extraction is pharmacologically active against systemic helminths. Albendazole is more completely absorbed, but is almost undetectable in plasma due to its rapid conversion to an active sulphoxide metabolite. This compound may well become the drug of choice for the chemotherapy of echinococcosis. Levamisole, the 1-isomer of tetramisole, is rapidly and completely absorbed, but has not been widely used in systemic helminthiases because of severe side effects associated with prolonged dosage.

Diethylcarbamazine is microfilaricidal against Onchocerca volvulus, but its use has been associated with major adverse effects resulting from its action on the microfilariae. These effects are related to the concentration of the drug in the plasma which, in turn, is influenced by urinary pH. The elimination half-life of diethylcarbamazine is prolonged and renal clearance reduced in alkaline urine. Under these conditions the microfilaricidal effect is enhanced, but the adverse reactions to treatment are more severe.

Suramin is the only available antifilarial agent with macrofilaricidal activity. It has a long elimination half-life (36 to 54 days), and is highly (99.7%) bound to plasma protein which limits its removal from the blood. Ivermectin is a macrocyclic lactone with microfilarial activity which persists long after the drug has been eliminated from the plasma, suggesting that its mode of action is not related directly to its concentration in the systemic circulation.

Metrifonate is an organophosphate, active against Schistosoma haematobium without major side effects. It is also microfilaricidal against Onchocerca volvulus but produces a greater degree of systemic side effects than diethylcarbamazine. The drug is well absorbed but is transformed into an active compound, dichlorvos, by a non-enzymic process. Both metrifonate and dichlorvos are eliminated rapidly by the kidneys.

The schistosomicides niridazole, oxamniquine and praziquantel are all extensively metabolised. Niridazole and praziquantel are highly extracted on the first-pass through the liver. Oxamniquine is metabolised by the enzymes in the gut wall, but is relatively poorly cleared by the liver. All 3 compounds are rapidly eliminated. The presence of intra- and extrahepatic shunts in patients with hepatosplenic schistosomiasis might lead to reduced clearance and increased bioavailability of niridazole and praziquantel, necessitating dosage reductions in these subjects.