Source: European Medicines Agency (EU) Revision Year: 2013 Publisher: SUPPLIER: Eisai Co., Ltd., 4-6-10 Koishikawa, Bunkyo-ku, Tokyo 112-8088, Japan, Phone: +81 3 3817 3684, Fax: +81 3 3811 2710, Email: mailto: Eisai-asia_safety@hhc.eisai.co.jp
Pharmacotherapeutic group: Antihelmintics
ATC code: P02CB02
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.
Administration of diethylcarbamazine citrate (6 mg/kg) and albendazole 400 mg resulted in a decrease in blood microfilariae (See Clinical efficacy and safety section below).
The efficacy of diethylcarbamazine citrate was first established as a 12-day treatment for lymphatic filariasis; however meta-analysis across studies has indicated that a single dose is as effective as a 12-day treatment regimen in clearance of microfilariae from the blood. Decrease in blood microfilariae is the standard measure of efficacy in lymphatic filariasis.
The improved efficacy of two-drug regimens in treating subjects with microfilariae supported the use of diethylcarbamazine citrate and albendazole in single-dose, once-yearly treatment to reduce microfilaraemia in endemic populations and this is one of the regimens used in the MDA programmes.
The effectiveness of MDA programmes has been demonstrated in studies conducted in India, Papua New Guinea, Vanuatu and Egypt. For example, the Ramaiah KD et al., 2011 study suggests that six rounds of once-yearly mass administration of single doses of diethylcarbamazine citrate and albendazole, with 60% to 70% treatment coverage, is likely to achieve total interruption of transmission and elimination of lymphatic filariasis in the majority of villages. An efficacy summary of the microfilariae clearance observed in several field studies in the MDA programmes is presented in the following table:
| MDA programmes* | ||||
|---|---|---|---|---|
| Study | Treatment Arm | Number of Subjects | Microfilaraemia | |
| Baseline | Endpoint | |||
| Ramaiah KD et al., 2011 Five villages (South India) | 6 mg/kg DEC plus 400 mg ALB | 5622 60% to 70% of the eligible population (>15 kg body weight) | Baseline Mf prevalence rate ranged from 4.27% (10/234) to 11.36% (5/44) in the 5 study villages; the overall prevalence was 8.10% (63/778) (CI: 6.18 to 10.01). | After 6 rounds of MDA: Overall prevalence fell to 1.01% (8/791) (CI: 0.31 to 1.71), equivalent to microfilaraemia clearance rate of 88%. The Mf prevalence fell to <0.5% in 4 of the 5 villages and it was 2.93% (6/205) in the fifth village. Two villages achieved 0% prevalence after the fourth round of MDA and maintained the same level thereafter. Reduction in Mf prevalence (P<0.05). |
| Weil GJ et al., 2008 Four villages (Papua New Guinea) | 6 mg/kg DEC plus 400 mg ALB | 971 to 1000 per cycle (compliance of 72.9%) | Baseline Mf prevalence rate was 18.6%. | After 3 rounds of MDA: Mf clearance rates in infected persons were 76%, 95.2%, and 98.1% after 1, 2, and 3 rounds of MDA, respectively. P=0.013 The difference in baseline Mf counts between the two groups was statistically significant (P<0.001). |
| Rajendran R et al., 2006 Two communities (South India) | 6 mg/kg DEC plus 400 mg ALB 6 mg/kg DEC alone | DEC plus ALB: 703 to 1724 per cycle (coverage of 72.7%-94.4%; compliance of 52.4%-83.6%) DEC alone: 827 to 1432 per cycle (coverage of 67.9%- 98.9%; compliance of 42.4%-80.3%) | The Mf prevalence in the 2 to 25 years age group was 5.21% in DEC plus ALB arm and 4.34% in DEC alone arm | After 3 rounds of MDA: The percentage reductions in Mf prevalence were higher in the DEC plus ALB arm (72.4% versus 51.4%). P<0.05 in both arms. |
| Ramzy RM et al.,2006 Four villages (Egypt) | 6 mg/kg DEC plus 400 mg ALB | Approx 1800 | Microfilaraemia prevalence rates were much higher in Giza than in Qalubyia (11.5 [95% CI: 10.2 to 12.8] and 3.1 [95% CI: 2.4 to 3.8], respectively). | After 5 rounds of MDA: In Giza, prevalence rates of microfilaraemia fell from 11.5% to 1.2%. In Qalubyia, prevalence rates of microfilaraemia fell 13.6% to 3.1%. P<0.0001 in both Giza and Qalubyia |
| Fraser M et al., 2005 Eight sentinel sites (Vanuatu) | 100 to 400 mg DEC (depending on age) plus 400 mg ALB | 561 (average of 72% of the eligible population) | Baseline: Microfilaraemia prevalence was 12% | After 2 rounds of treatment: Prevalence of microfilaraemia was reduced by 93% (from 12% to 0.8%) Reduction in prevalence of microfilaraemia (P<0.001) |
* Studies used various formulations of diethylcarbamazine.
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 Cmax value was 598 (±84) ng/ml and the corresponding value for AUC was 7950 (±1660) ng.h/ml. The mean (±SD) diethylcarbamazepine Tmax value was 2.25 (± 1.17) hours.
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.
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.
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.
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 Citrate Tablets. However, diethycarbamazine citrate is a well-established drug with an extensive record of clinical use.
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