Diethylcarbamazine Other names: Carbilazine

Diethylcarbamazine citrate is a synthetic piperazine derivative with an antihelmintic action.

MDA of diethylcarbamazine citrate has potential to interrupt the parasitic life cycle by destruction of microfilariae which are essential for host to vector transmission of the parasite. The basic principle of MDA is to suppress microfilaraemia to levels at which transmission is not possible.

The mode of action of diethylcarbamazine citrate is not clearly known. Diethylcarbamazine citrate can be best described as a potent anti-microfilaraemic agent with variable macrofilaricidal properties. The drug is known to exert its effect directly on the parasite and also achieve parasite killing by activating the host immune response. Several potential modes of action of diethylcarbamazine citrate leading to microfilariae killing have been identified:

• Overstimulation of the neuromuscular system of the parasites and increased motility, inhibition of vital parasite metabolic enzymes, activation of surface membrane complement, activation of eosinophils and release of eosinophil-derived cationic proteins, enhanced eosinophil-dependent antibody mediated destruction of parasites and increased adhesion of parasites to phagocytic and antibody producing cells.
• Inhibition of acetylcholinesterase production by parasites, leading to increased levels of lysosomal enzymes β-glucuronidase and acid phosphatase that are involved in phagocytosis.
• Release of nitric oxide as evidenced by increased levels of nitrite and nitrates.
• Changes in arachidonic acid metabolism in the parasite and the host that alter adhesiveness of the parasite.

The mode of action of diethylcarbamazine citrate on adult worms is less well documented. However, there is sufficient evidence to suggest that diethylcarbamazine is macrofilaricidal. Degenerating adult worms have been demonstrated in lymph nodes post-treatment. It is also well known that the macrofilaricidal effects are inconsistent.

Diethylcarbamazine citrate was found to have effects on the arachidonic acid and cyclooxygenase metabolic pathways and COX-1 pathway of filaria. It has also been determined that inducible nitric oxide is essential for the rapid sequestration of microfilariae by diethylcarbamazine citrate. It has been suggested that as diethylcarbamazine citrate alters arachidonic acid metabolism in microfilariae (and in host endothelial cells), these changes may result in vasoconstriction and amplified endothelial adhesion, leading to immobilization of microfilarial parasites, enhanced adherence, and cytotoxic activity by host platelets and granulocytes. This would represent activation of the innate, nonspecific immune system, independent of the adaptive, antigen-specific, immune response.

Pharmacodynamic effects

Decrease of microfilariae in blood

Administration of diethylcarbamazine citrate (6 mg/kg) and albendazole 400 mg resulted in a decrease in blood microfilariae.

Absorption and bioavailability

Diethylcarbamazepine is readily absorbed following oral administration. Bioavailability is between 80 and 85%. Following single dose administration of one diethylcarbamazine tablet in healthy volunteers in the fed state, the mean (±SD) diethylcarbamazepine C_max value was 598 (±84) ng/ml and the corresponding value for AUC was 7950 (±1660) ng.h/ml. The mean (±SD) diethylcarbamazepine T_max value was 2.25 (±1.17) hours.

Distribution

Diethylcarbamazine is widely distributed in tissues and is mainly excreted in the urine unchanged and as the metabolite, diethylcarbamazine N-oxide. Urinary excretion, and hence plasma half–life, is dependent on urinary pH. About 5% of a dose is excreted in the faeces.

Metabolism

In rats and monkeys after an intravenous dose, 10-20% is excreted in the urine as unchanged drug, most of which is excreted in the first 3 hours. Metabolites more slowly eliminated include N-ethyl-4-methyl-1-piperazine-carboxamide (MEC) and their N-oxides, 4-methyl-piperazine-carboxamide and N,N-diethyl-1-piperazine-carboxamide. In vivo most of the metabolites are active on microfilariae and both N-oxides active on adults and infective larvae. The antifilarial action of DEC is swift and of short duration. This action is prolonged by the activity of metabolites, especially the N-oxides.

Elimination

Diethylcarbamazine elimination is primarily through renal clearance, which accounts for around 50% of the total plasma clearance. The remaining clearance is via metabolism, leading to a number of metabolites, which are also renally cleared. Given that the major elimination pathway is renal clearance and that metabolic clearance is via several routes, genetic polymorphisms of drug metabolizing enzymes are very unlikely to have any clinically relevant consequences. This is borne out by the fact that there are no reported significant drug-drug interactions with diethylcarbamazine citrate which would likely be evident if modulation of metabolic clearance was an important factor in determining systemic exposure.

The PK of diethylcarbamazine citrate was not altered by timing of administration (morning versus evening).

The elimination half-life and area under the plasma concentration-time curve of diethylcarbamazine were significantly increased when an alkaline urinary pH was maintained compared with the values of these parameters obtained on a second occasion when an acidic urinary pH was maintained. This effect is unlikely to be of clinical relevance in the MDA program.

Renal impairment

Results in patients with chronic renal impairment and in healthy subjects given a single 50 mg oral dose of diethylcarbamazine indicated that the plasma half–life of diethylcarbamazine is prolonged and its 24-hour urinary excretion is considerably reduced in those with moderate to severe renal impairment. No significant correlations were observed between age, sex or weight and renal function, but diethylcarbamazine excretion did appear to decrease with increasing urinary pH.

Nonclinical studies have not been performed with diethylcarbamazine. However, diethycarbamazine citrate is a well-established drug with an extensive record of clinical use.