Ivermectin

Summary

Synopsis

Ivermectin, a derivative of avermectin B, is an orally effective microfilaricidal agent. It is the current drug of choice for treating patients infected with the nematode Onchocerca volvulus, which is a major cause of blindness in inhabitants of some tropical areas. Ivermectin is administered orally as a single dose of 150 βg/kg given annually. Skin and ocular microfilarial counts are dramatically reduced after the first dose, with some evidence for a resulting decrease in transmission of infection by the blackfly vector. With the exception of rare serious reactions such as severe systemic postural hypotension, ivermectin is generally well tolerated. The drug has the clear advantages of ease of administration and better tolerability compared with diethylcarbamazine and suramin, agents previously used to treat onchocerciasis.

Thus, ivermectin is suitable for inclusion in mass treatment programmes and is the best therapeutic option presently available to combat onchocerciasis. As such it provides hope for many thousands of people at risk of becoming blind, and represents a major contribution to tropical medicine.

Pharmacological Properties

Since O. volvulus is difficult to maintain under laboratory conditions, the in vitro and in vivo micro- and macrofilaricidal activity of ivermectin has also been investigated in other filarial species of nematode. Ivermectin concentrations of 10 to 50 /ug/L had no significant effect on O. volvulus microfilariae in vitro Higher concentrations (5 to 30 mg/L) killed microfilariae with 100% mortality achieved at 30 mg/L. In vitro, low concentrations of ivermectin (3.14 × 10⁻⁸ to 1 × 10⁻⁷ mol/L) inhibited motility of O. gutturosa macrofilariae to a limited extent; immobilisation was achieved at a concentration of 1.25 × 10⁻⁵ mol/L.

In humans, a single oral 100 to 200 Mg/kg dose markedly reduced numbers of skin and ocular tissue O. volvulus microfilariae and decreased microfilariae motility. After ivermectin treatment, most remaining viable microfilariae are found in the subcuticular skin layer; in untreated patients microfilariae are found predominantly in the upper lmm of skin.

The mechanism of action of ivermectin is not fully understood but a number of possibilities have been proposed including a direct toxic effect (possibly mediated by potentiation of the inhibitory neurotransmitter GABA) and/or inhibition of intrauterine microfllarial development and release from female adult worms.

In healthy subjects peak plasma ivermectin concentrations of about 50 μg/L are recorded approximately 4 hours after the administration of a 12mg dose in either tablet or capsule formulation. There is evidence that absorption is greater if the drug is administered in an oral aqueous ethanol solution. Little is known regarding the distribution and elimination of ivermectin although 2 metabolites have been identified in humans. The following pharmacokinetic variables have been reported in healthy subjects: elimination half-life (28 hours), volume of distribution (46.9L), plasma protein binding (93%) and oral clearance (1.2 L/h).

Clinical Efficacy

Large scale community trials in tens of thousands of patients with onchocerciasis, including children older than 5 years, have demonstrated that ivermectin is effective and suitable for mass treatment. Skin microfilariae counts decreased by 85 to 95% when measured 2 months after single dose treatment with oral ivermectin 150 μg/kg; such reductions are clinically significant in patients with heavy infestation.

Dose-finding and comparative trials indicate that parasite counts decrease rapidly within 2 to 8 days of a 100 to 200 μg/kg dose, and remain suppressed for several months. Although levels rise gradually toward baseline thereafter, at 12 months skin microfilariae counts are only one-tenth of pretreatment values.

Reductions in ocular parasite counts (in the cornea and anterior chamber) tend to follow a course parallel to that in skin, although the rate of decrease is slower. At 4 months ocular levels had diminished by 80% in a large community trial. However, the finding that after several months ocular microfilariae counts rose to about 30% of pretreatment levels led some investigators to advocate a 6-monthly, rather than a once yearly, treatment programme.

Ivermectin as a single dose is at least as effective as diethylcarbamazine administered in a complicated multiple dose regimen, and is considerably better tolerated. Although both drugs produce similar patterns of microfilarial elimination from skin and eyes, ivermectin causes a more sustained suppression of microfilariae counts.

By reducing the prevalence of microfilariae amongst a mass population, ivermectin therapy also influences the rate of disease transmission. In one large trial the reduction in availability of microfilariae for transmission was estimated to be 68 to 78%, consistent with a decrease in vector infection of 65 to 85% as evidenced by entomological results. These effects are reflected in reductions in overall microfilarial load in both treated and untreated patients in mass treatment programmes and, in 1 trial, a decrease in the annual rate of new infections in children.

Tolerability

Almost all of the adverse effects which occur during ivermectin treatment are a result of the patient’s immune response to dead microfilariae, and usually appear within 3 days of the dose. The most common of these include myalgia, rash, node tenderness, swelling of nodes, joints, limbs or face, itching, fever and chills. These are usually of mild to moderate severity and generally respond to analgesics or antihistamines. The severity of the response is directly related to the initial degree of O. volvulus infestation.

The incidence of adverse effects among patients administered ivermectin is difficult to quantify because of variability in reporting methods. Although small samples have reported incidence rates of as high as 35%, this is probably not representative. In a mass treatment programme involving >50 000 subjects, 9% had an adverse effect after the first dose, and the rate was 15% amongst more than 7400 Ghanaian patients in a separate trial.

Ivermectin does not cause severe ocular complications in patients with onchocerciasis. No changes in visual acuity or appearance of punctate opacities have occurred with ivermectin, and in this respect it is superior to diethylcarbamazine. Similarly, ivermectin is much less likely to cause the potentially fatal Mazzotti reaction associated with diethylcarbamazine, although there have been reports of severe postural hypotension (occurring in 37 of about 14000 patients in 1 large trial) and other rare but serious reactions in patients receiving ivermectin.

Dosage and Administration

Ivermectin is administered as a single oral dose, usually 150 A*g/kg. Annual re-treatment (using the same initial dosage) is required. There is some evidence from clinical trials that ivermectin may be more effective in patients with heavy ocular involvement when given 6-monthly rather than yearly.