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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 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.
Volunteers were recruited in 3 groups based on body weight. Plasma concentrations of ivermectin were measured through HPLC up to 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.
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. 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.
Data Availability: All relevant data are within the paper and its Supporting Information files. Funding: The study was funded in full by Exeltis France. Grant The funders participated in study design and decision to publish through the co-authors SG and EC. Competing interests: 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.
The control of Neglected Tropical Diseases NTDs has in ivermectin IVM the most significant tool among all the drugs used for morbidity control and interruption of transmision. Due to its impact on onchocerciasis and lymphatic filariasis LF , this macrocyclic lactone has been used in millions of individuals mainly through the Mectizan Donation Program, achieving goals of breaking transmission in several countries and putting those landmark achievements in the horizon of several other countries [ 1 — 3 ].
The very basic approach to the use of IVM consists in its distribution to entire communities through annual or biannual mass drug administration MDA campaigns provided its excellent safety profile [ 4 ], whose only significant severe adverse reaction has been determined by its use in Loa loa infected individuals due to the life-threatening adverse events in this group [ 5 ]. The large experience on the use of IVM in the veterinary world, where it was first introduced in and the growing perception of its capabilities in human disease since its introduction in has widened its indications to a growing number of infectious diseases.
The wide spectrum of action of IVM includes treatment of Strongyloides stercoralis , Gnathostoma spp , Mansonella streptocerca and ectoparasites such as head lice or scabies [ 1 , 6 ]. Moreover, it has been evaluated in co-administration with albendazol for the treatment of soil transmitted helminthiasis STH showing an increased efficacy compared to albendazole stand-alone against Trichuris trichiura [ 7 , 8 ], therefore increasing the feasibility of achieving transmission interruption, as shown in modelling exercises [ 9 ].
Due to its alternative mechanism of action, the addition of IVM to a benzimidazole based regimen lowers the threat of emergence of drug resistance [ 10 ], as suggested in modelling studies conducted in veterinary medicine [ 11 ]. Furthermore, the recent finding that the endectocide effect of IVM reduces the survival of Anopheles mosquitoes that feed on an IVM treated person after a single standard oral dose, supports the integration of IVM-based interventions for the control of multiple tropical infectious diseases [ 12 , 13 ].
Along with its favorable pharmacodynamic aspects, the pharmacokinetic characteristics of IVM also appear to be opening possibilities to expand its use and access. It has rapid oral absorption, high liposolubility and is widely distributed in the body [ 14 ]. Following a standard oral dose in healthy humans, IVM reaches peak plasma levels at 3.
It is metabolized in the liver through the cytochrome P system and excreted almost exclusively in feces [ 14 , 17 ]. Despite its widespread use, there are relatively few studies on the pharmacokinetics of IVM in humans [ 18 ] and a full understanding of the relationship between drug levels and activity is also missing, including the mechanisms related to remnant activity beyond time points when significant drug levels are measured, as has been demonstrated in veterinary and vector-borne diseases studies [ 19 , 20 ].
Regardless of its safety profile and pharmacokinetic features, IVM is prescribed for all its indications in weight or height based regimens, which difficult its administration in MDA interventions and introduces the risk of under-dosing [ 21 ]. A fixed and high dose regimen which takes advantage of the wide therapeutic index of IVM is an attractive alternative for improving the distribution and therefore potentially increasing coverage rates of treatment campaigns as has been the case for primaquine in the treatment of malaria [ 22 ].
Moreover, a safe and efficacious fixed-dose IVM in formulations different than the traditional 3 and 6 mg tablets would be required if co-formulated with other anthelmintics such as albendazole.
This study was designed to evaluate the safety and pharmacokinetic profile of 3 dosing regimens of IVM in 54 healthy adult volunteers stratified in 3 weight groups in an open-label, randomized, crossover phase I clinical trial performed under fasting conditions.
The study was single dose, three-period, comprising 3 experimental phases of treatment with different doses of IVM. Three groups of 18 healthy volunteers with different weights participated in this trial.
All participants in each group received three sequential treatments with mL of mineral water. A fourteen-day washout period between each dosing was used Fig 1. At the beginning of the study, the subjects were allocated to a randomization number following a procedure of consecutive assignment following a randomization list generated using Windows SPSS software IBM Corp.
Released From the coefficients of variation of the truncated AUC obtained Nevertheless, the proposed sample size of 18 volunteers per group was within the range cited in several publications about the pharmacokinetic evaluation of IVM [ 15 , 16 , 24 ] and it was considered adequate for the analysis of the main objective of the study. Participants were male and female subjects aged between 18 and 45 years meeting the inclusion criteria: i No abnormal findings in medical history and physical examination, ii Normal laboratory tests hematology evaluations, blood chemistry and urinalysis , vital signs systolic and diastolic blood pressure, heart rate and temperature and ECG record, iii Not having participated in another clinical trial during the 3 months before starting the current trial and iv Not having donated blood during the 8 weeks prior to starting the current trial.
Female volunteers had to use reliable contraceptive measures not containing hormones. They also agreed to abstain from beverages or food containing grapefruit for 14 days prior to the first study drug administration until study completion. None of the volunteers was at risk of being affected by Loa loa or other filarial infections.
In each period after fasting overnight for 10 h, subjects received the assigned treatment described above. During the experimental phase in each period, volunteers were allowed to drink water ad libitum and eat solids from 4 hours after dosing. Bioanalytical determinations were performed by Anapharm Europe S. The calibration curve ranged from 0. Within-run accuracy at 0. Between-run precision was not higher than 5. The Per-Protocol population, defined as all randomized subjects who met the entry criteria, received all study medication, completed the study and did not present protocol violations was used for the pharmacokinetic analysis.
Missing samples were treated as non-reportable concentration. C max was obtained directly from the plasma concentration—time data.
The safety population defined as all randomized subjects who took at least one dose of the study medication was used for safety analyses.
Moreover, a complete physical examination and ECG were assessed at the screening visit and at the end of each the three periods. All adverse events observed either by the investigator or reported by the subjects themselves during the clinical study were also recorded and evaluated by the investigator for severity and relationship to the study drug.
The severity of each AE was graded according to the following categories: mild, moderate, or severe. The study adhered to the updated Declaration of Helsinki [ 28 ] and was conducted according to rules of Good Clinical Practice [ 29 ]. All subjects provided written informed consent to participate in the study after the nature and purpose of the study was fully explained to them and received stipends for their collaboration.
Descriptive statistics were calculated for all pharmacokinetic parameters as well as a comparison between treatments were performed for all pharmacokinetic parameters. A comparative analysis of bioavailability was applied for the parameters determining exposition in extent [AUC 0 t ] and rate of absorption [C max ] without dose correction.
Three four-way analysis of variance ANOVA for the crossover design were used to assess the effect of dosage, periods, sequences, and subjects-within-sequences on the same parameters. For comparison of the safety and tolerability of IVM between fixed doses FD18 vs FD36 and between fixed doses and WA-ref adjusted by body weight for each group, an ANOVA and posterior paired analysis with contrast was performed for the parameters obtained in the vital signs, ECG, hematology evaluations, blood chemistry and urianalyses.
Study population initially included 27 female and 30 male caucasian volunteers without clinical evidence of laboratory, ECG or vital sign abnormalities. None of the randomized subjects were smokers. A description of the most important demographic parameters and other baseline data is shown in Table 1. BMI: body mass index. Fifty-seven volunteers were included in the study and received at least one dose of study drug. After recruitment, one volunteer withdrawn due to personal reasons and two were excluded one for for a slightly prolonged partial thromboplastin time and the other by protocol deviation in treatment administration and did not complete the study.
A total of 54 volunteers completed the study Fig 3. Flow diagram of the study. No abnormal result or significant differences were found between biochemistry at baseline and after the administration of IVM in any of the three study arms. A slight decrease in Haemoglobin Hb levels was observed after administration of IVM in the three study arms. Hb decreased from However, no signs or symptoms of anemia were detected in any of the study participants. The main electrocardiographic parameters were not affected by the administration of IVM.
Systemic blood pressure measurements were not affected by treatment administration. A total of 33 treatment emergent adverse events were reported by 22 subjects who received at least one dose of the study medication. Eleven adverse events were reported by 10 subjects after receiving WA-ref, 9 were reported by 9 subjects after receiving FD18 and 13 were reported by 13 subjects after FD36 Table 2. The most frequent adverse event described by study participants was headache 6.
Of the 33 adverse events reported, 10 were graded as mild and 23 were graded as moderate. The type and distribution of adverse events by study group are shown in Table 3. Fifteen adverse events were considered possibly related to the investigational products and 18 not related to the investigational products.
It was necessary to administer concomitant medication on 14 subjects due to appearance of adverse events Table 2. Since the results were not significantly altered, we present the main results of the study including all 54 participants. The pharmacokinetic parameters of IVM in the three study groups are shown in Table 4.
Fig 4 shows the mean IVM plasma concentrations in the three treatment arms. Insert describe details of the time points within the initial 36 hours. When comparing the systemic bioavailability AUC 0 t and C max of WA-ref with the other two study groups using fixed doses, we observed an overall increase in AUC 0 t of 2. These higher values were observed in C max as well, showing a similar increase of 4.
REVECTINA BULA PDF
Barcelona, Spain. IIB Sant Pau. 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 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.
Revectina (Ivermectina) - Bula - 4
Pediculose: dermatose causada pelo Pediculus humanus capitis. Ivermectin for human strongyloidiasis and other intestinal helminthes. Treatment of Strogyloides srtercoralis infection with ivermectin compared with albendazole: results of an open study of 60 cases. Transactions of the Royal Society of Tropical medicine and Hygiene, v. Pediatr Mod, v. A comparative trial of a single-dose ivermectin versus three days of albendazole for treatment of Strogyloides stercolaris and other soil-transmitted helminth infections in children.
Revectina (Ivermectina) - Bula - 2