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      Safety and pharmacokinetic profile of fixed-dose ivermectin with an innovative 18mg tablet in healthy adult volunteers

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          Abstract

          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.

          Trial registration

          ClinicalTrials.gov NCT03173742.

          Author summary

          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.

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          Most cited references28

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          Safety, tolerability, and pharmacokinetics of escalating high doses of ivermectin in healthy adult subjects.

          Safety and pharmacokinetics (PK) of the antiparasitic drug ivermectin, administered in higher and/or more frequent doses than currently approved for human use, were evaluated in a double-blind, placebo-controlled, dose escalation study. Subjects (n = 68) were assigned to one of four panels (3:1, ivermectin/placebo): 30 or 60 mg (three times a week) or 90 or 120 mg (single dose). The 30 mg panel (range: 34 7-594 microg/kg) also received a single dose with food after a 1-week washout. Safety assessments addressed both known ivermectin CNS effects and general toxicity. The primary safety endpoint was mydriasis, accurately quantitated by pupillometry. Ivermectin was generally well tolerated, with no indication of associated CNS toxicity for doses up to 10 times the highest FDA-approved dose of 200 microg/kg. All dose regimens had a mydriatic effect similar to placebo. Adverse experiences were similar between ivermectin and placebo and did not increase with dose. Following single doses of 30 to 120 mg, AUC and Cmax were generally dose proportional, with t(max) approximately 4 hours and t1/2 approximately 18 hours. The geometric mean AUC of 30 mg ivermectin was 2.6 times higher when administered with food. Geometric mean AUC ratios (day 7/day 1) were 1.24 and 1.40 for the 30 and 60 mg doses, respectively, indicating that the accumulation of ivermectin given every fourth day is minimal. This study demonstrated that ivermectin is generally well tolerated at these higher doses and more frequent regimens.
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            Mass Drug Administration for Scabies Control in a Population with Endemic Disease.

            Scabies is an underrecognized cause of illness in many developing countries. It is associated with impetigo, which can lead to serious systemic complications. We conducted a trial of mass drug administration for scabies control in Fiji.
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              Unresolved issues in anthelmintic pharmacology for helminthiases of humans.

              Helminth infections are an important constraint on the health and development of poor children and adults. Anthelmintic treatment programmes provide a safe and effective response, and increasing numbers of people are benefitting from these public health initiatives. Despite decades of clinical experience with anthelmintics for the treatment of human infections, relatively little is known about their clinical pharmacology. All of the drugs were developed initially in response to the considerable market for veterinary anthelmintics in high- and middle-income countries. In contrast, the greatest burden caused by these infections in humans is in resource-poor settings and as a result there has been insufficient commercial incentive to support studies on how these drugs work in humans, and how they should best be used in control programmes. The advent of mass drug administration programmes for the control of schistosomiasis, lymphatic filariasis, onchocerciasis and soil-transmitted helminthiases in humans increases the urgency to better understand and better monitor drug resistance, and to broaden the currently very narrow range of available anthelmintics. This provides fresh impetus for developing a comprehensive research platform designed to improve our understanding of these important drugs, in order to bring the scientific knowledge base supporting their use to a standard equivalent to that of drugs commonly used in developed countries. Furthermore, a better understanding of their clinical pharmacology will enable improved therapy and could contribute to the discovery of new products. Copyright 2009 Australian Society for Parasitology Inc. Published by Elsevier Ltd. All rights reserved.
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                Author and article information

                Contributors
                Role: ConceptualizationRole: Formal analysisRole: InvestigationRole: MethodologyRole: SupervisionRole: Writing – original draftRole: Writing – review & editing
                Role: Data curationRole: Formal analysisRole: InvestigationRole: MethodologyRole: ValidationRole: Writing – original draftRole: Writing – review & editing
                Role: Data curationRole: Formal analysisRole: MethodologyRole: Project administrationRole: Supervision
                Role: Data curationRole: Formal analysisRole: Methodology
                Role: InvestigationRole: Project administrationRole: Resources
                Role: Funding acquisitionRole: Methodology
                Role: ConceptualizationRole: MethodologyRole: Resources
                Role: ConceptualizationRole: Formal analysisRole: Funding acquisitionRole: InvestigationRole: MethodologyRole: Project administrationRole: Writing – original draft
                Role: Editor
                Journal
                PLoS Negl Trop Dis
                PLoS Negl Trop Dis
                plos
                plosntds
                PLoS Neglected Tropical Diseases
                Public Library of Science (San Francisco, CA USA )
                1935-2727
                1935-2735
                18 January 2018
                January 2018
                : 12
                : 1
                : e0006020
                Affiliations
                [1 ] Barcelona Institute for Global Health, ISGlobal-CRESIB, Universitat de Barcelona. Barcelona, Spain
                [2 ] CIM-Sant Pau. IIB Sant Pau. Institut de Recerca de l’Hospital de la Santa Creu i Sant Pau. Barcelona, Spain
                [3 ] Pharmacology and Therapeutics Department, Universitat Autònoma de Barcelona (UAB), Bellaterra, Spain
                [4 ] ExeltisPharma, Chemo group. Madrid, Spain
                [5 ] Fundacion Mundo Sano, Buenos Aires, Argentina
                [6 ] Instituto de Investigaciones en Enfermedades Tropicales, Universidad Nacional de Salta/CONICET, Oran, Argentina
                McGill University, CANADA
                Author notes

                Yes. I have read the journal's policy and the authors of this manuscript have the following competing interests: EC and SG are members of Chemo Group, which includes Liconsa, the manufacturer of the study drug and Exeltis France, the funding source.

                Author information
                http://orcid.org/0000-0001-9054-1211
                Article
                PNTD-D-17-01080
                10.1371/journal.pntd.0006020
                5773004
                29346388
                9f730e73-1b4a-4840-8a67-055283febf4c
                © 2018 Muñoz et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 4 July 2017
                : 6 October 2017
                Page count
                Figures: 4, Tables: 5, Pages: 16
                Funding
                Funded by: Exeltis France
                Award ID: 2015-005690-20
                Award Recipient :
                The study was funded in full by Exeltis France. Grant # 2015-005690-20. The funders participated in study design and decision to publish through the co-authors SG and EC.
                Categories
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                All relevant data are within the paper and its Supporting Information files.

                Infectious disease & Microbiology
                Infectious disease & Microbiology

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