Ivermectin is a pivotal drug for the control of onchocerciasis and lymphatic filariasis, which is increasingly identified as a useful drug for the control of other Neglected Tropical Diseases. Its role in the treatment of soil transmitted helminthiasis through improved efficacy against Trichuris trichiura in combination with other anthelmintics might accelerate the progress towards breaking transmission. Ivermectin is a derivative of Avermectin B1, and consists of an 80:20 mixture of the equipotent homologous 22,23 dehydro B1a and B1b. Pharmacokinetic characteristics and safety profile of ivermectin allow to explore innovative uses to further expand its utilization through mass drug administration campaigns to improve coverage rates. We conducted a phase I clinical trial with 54 healthy adult volunteers who sequentially received 2 experimental treatments using a new 18 mg ivermectin tablet in a fixed-dose strategy of 18 and 36 mg single dose regimens, compared to the standard, weight based 150–200 μg/kg, regimen. Volunteers were recruited in 3 groups based on body weight. Plasma concentrations of ivermectin were measured through HPLC up to 168 hours post treatment. Safety data showed no significant differences between groups and no serious adverse events: headache was the most frequent adverse event in all treatment groups, none of them severe. Pharmacokinetic parameters showed a half-life between 81 and 91 h in the different treatment groups. When comparing the systemic bioavailability (AUC 0 t and C max) of the reference product (WA-ref) with the other two study groups using fixed doses, we observed an overall increase in AUC 0 t and C max for the two experimental treatments of 18 mg and 36 mg. Body mass index (BMI) and weight were associated with t 1/2 and V/F, probably reflecting the high liposolubility of IVM with longer retention times proportional to the presence of more adipose tissue. Systemic exposure to ivermectin (AUC 0 t or C max) was not associated with BMI or weight in our study. These findings contribute to further understand the pharmacokinetic characteristics of ivermectin, highlighting its safety across different dosing regimens. They also correlate with known pharmacokinetic parameters showing stable levels of AUC and C max across a wide range of body weights, which justifies the strategy of fix dosing from a pharmacokinetic perspective.
Current efforts for the control of poverty-related diseases provide drug treatments through mass drug administration (MDA) as a key component. Ivermectin is an antiparasitary drug which has been used to fight some of these diseases, and millions of treatments have been distributed with a favorable toxicity profile. The dosing strategy of ivermectin is based on weight, which in view of the safety characteristics of ivermectin might not be necessary, while a fix dosing strategy might improve logistics and access to the drug to those who need it. This study was conducted in healthy adult volunteers in which we compared 3 treatment regimens: the weight-based reference standard versus 2 experimental regimens of fix-dose 18 and 36 mg using 18 mg tablets. All 54 volunteers received the 3 treatments sequentially. The results confirmed that the fixed-dose regimen (both 18 mg and 36 mg) are as safe as the standard dosage and could justify the use of fix dosing regimens rather than the current weight based strategy.