Feb 21, 2021
DR G EVAL ATIO
Drugs 42 (4): 640-658, 1991 0012-6667/91 /00 I0-0640/$09 .50/0 © Adis International Limited . All rights reserved .
Ivermectin A Review of its Antifilarial Activity, Pharmacokinetic Properties and Clinical Efficacy in Onchocerciasis
Karen L. Goa, Donna Mc'Tavisn and Stephen P. Clissold Adis International Limited , Auckland, New Zealand
Various sections of the manuscript reviewed by: A.M. Breckenridge, The University of Liverpool, Liverpool, England; K.Y. Dadzie, Onchocerciasis Control Programme in West Africa, World Health Organization , African Region, Ouagadougou, Burkina Faso; S. Dial/o, Faculte de Medecine et de Pharmacie, Service de Parasitologie, Universite Cheikh Anta Diop de Dakar, Dakar, Senegal; B. Duke, River Blindness Foundation, Houston, Texas, USA; G. Edwards, Department of Pharmacology and Therapeutics, The University of Liverpool, Liverpool, Eng- land; H. Fukuda, Department of Pharmacology, College of Pharmacy, Nihon University , Chiba, Japan; T. Itoh, Department of Clinical Pharmacology, Faculty of Medicine, Tottori University, Yonago, Japan; K. Matsumoto, Department of Pharmacology, College of Pharmacy , Nihon University , Chiba, Japan; H. Neu, Department of Medicine, Division ofInfectious Diseases, Collegeof Physicians and Surgeons of Columbia University, New York, New York, USA; H. Newland, Department of Ophthalmology , Hinders Medical Centre, Bedford Park, South Australia, Australia; E.A. Ottesen, Clinical Parasitology Section, National Institute of Allergy and Infectious Dis- eases, National Institutes of Health, Bethesda, Maryland, USA; H. Schulz-Key, Eberhard-Karls-Un iversitat Tub- ingen, Universitatsklinikum, Institut fur Tropemedizin, Tubingen, Federal Republic of Germany; H.R. Taylor, Department of Ophthalmology, Melbourne University, East Melbourne, Victoria, Australia; J. Whitworth , Trop- ical Health Epidemiology Unit, Department of Epidemiology and Populat ion Sciences, London School of Hygiene and Tropical Medicine, London, England.
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Summary I. Pharmacological Propert ies
l.l Antifilarial Activity 1.1.1 In Vitro and Animal Studies 1.1.2 Human Studies 1.1.3 Mechanism of Action
1.2 Pharmacokinetic Properties 2. Clinical Efficacy
2.1 Dose-Finding Studies 2.2 Comparisons with Diethylcarbamazine 2.3 Mass Treatment in Large Scale Community Trials
2.3.1 Effects of Ivermectin on Skin and Ocular Microfilarial Loads 2.3.2 Effect on Disease Transmission
3. Tolerability 3.1 General Reactions 3.2 Ocular Reactions
4. Dosage and Administration 5. Place of Ivermectin in Therapy
Ivermectin in Onchocerciasis: A Review
Ivermectin, a derivative of avermectin E, is an orallyeffective microfilaricidal agent. It is the current drugofchoice for treating patientsinfected with the nematodeOnchocerca volvulus, which is a major causeofblindness in inhabitants ofsome tropical areas.
Ivermectin is administered orallyas a singledoseof150p,g/kg givenannually. Skin and ocular microfilarial counts aredramatically reduced afterthefirst dose, withsome evidencefor a resulting decrease in transmission of infection by the blackjly vector. With the exception of rare serious reactions suchas severe systemicpostural hypotension, ivermectin is generally welltolerated. 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 suitablefor inclusion in mass treatment programmes and is the best ther- apeutic option presently available to combat onchocerciasis. As such it provides hopefor many thousands of people at risk of becoming blind, and represents a major contribution to tropical medicine.
Since 0. 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 Itg/L had no significant effect on 0. 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 X 10-8 to I X 10-7 mol/L) inhibited motility of O. gutturosa macrofilariae to a limited extent; immobilis- ation was achieved at a concentration of 1.25 X 10-5 mol/L,
In humans, a single oral 100 to 200 ltg/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 Imm 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 microfilarial development and release from female adult worms.
In healthy subjects peak plasma ivermectin concentrations of about 50 Itg/L are recorded approximately 4 hours after the administration of a l2mg dose in either tablet or capsule form- ulation. 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 al- though 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 Lzh),
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 ltg/kg; such reductions are clinicallysignificant 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 ltg/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
642 Drugs 42 (4) 1991
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, ivermect in 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 re- ductions in overall microfilarial load in both treated and untreated patients in mass treatment programm es and , in I trial , a decrease in the annual rate of new infections in children .
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 gen- erally 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 quan- tify because of variab ility 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 ina 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 I large trial) and other rare but serious reactions in patients receiving ivermectin.
Dosage and Administration
Ivermectin is administered as a single oral dose, usually ISO~gjkg. Annual re-treatment (using the same initial dosage) is required. There is some ev