Ivermectin (IVM), an antiparasitic drug approved by the Food and Drug Administration (FDA), is widely used to treat several neglected tropical diseases, including onchocerciasis, helminthiases, and scabies. Additionally, IVM has shown potential as a potent inhibitor of certain RNA viruses, such as SARS-CoV-2. However, IVM is highly hydrophobic, essentially insoluble in water, which limits its bioavailability and therapeutic effectiveness. The use of liposomes as drug carriers offers several advantages, including enhanced solubility for lipophilic drugs, passive targeting of immune system cells, sustained release, and improved tissue penetration. To address the limitations of IVM, including its poor solubility and bioavailability, liposomal formulations were developed using a combination of soyphosphatidylcholine (SPC), dioleylphosphatidylcholine (DOPC), cholesterol (Ch), and diethylphosphate (DCP) in two distinct molar ratios (1.85:1:0.15 and 7:2:1) via the ethanol injection method. The physicochemical properties of the placebo and IVM-loaded liposomes were extensively characterized in our earlier study, including the particle size, polydispersity index, and zeta potential. The present work adds a deeper level of investigation into how to effect cellular uptake and cytotoxicity in vitro of both free IVM and IVM-loaded liposomes in Vero E6 cells. The half-maximal cytotoxic concentrations (CC50) for free IVM and IVM-loaded liposomes were 10 μM and > 110 μM, respectively and the cellular uptake of IVM-loaded liposomes ranged from 13 to 60%, whereas free IVM showed a significantly lower uptake of only 2%. These results demonstrate that liposomal encapsulation effectively enhances IVM's cellular uptake while reducing its cytotoxicity, thus offering a promising strategy for improving the effectiveness of IVM.

The efficacy of the combination therapy of albendazole and ivermectin against Trichuris trichiura infection is higher in Tanzania than in Côte d'Ivoire. This study therefore aimed to investigate the difference between the population pharmacokinetics (PK) at these study sites and to determine if an exposure-response analysis could explain the low efficacy of the combination therapy in Côte d'Ivoire. Twenty-four participants (aged 12-19 years) receiving single doses of ivermectin (200 µg/kg) and albendazole (400 mg) were included in the population PK modeling. A regression analysis was performed to investigate the relationship between the reduction of fecal whipworm eggs and different exposure metrics (peak concentration, area under the plasma drug concentration-time curve [AUC], and time above a certain threshold). The PK profile of ivermectin was best described by a one-compartment model, first-order absorption, and no delay in absorption, with the absorption rate constant estimated as 0.26 per h, an apparent volume of distribution of 162.43 L, and an apparent clearance of 7.82 L/h. In Tanzania, all patients showed a very high reduction in egg count independent of exposure. In Côte d'Ivoire, a relationship was found between higher ivermectin exposure and egg reduction, although not statistically significant. There was no significant difference between the PK profiles at both study sites, despite a difference in clinical outcome. Model-based simulations indicate that higher ivermectin doses such as 400 and 600 µg/kg may be associated with reduced egg count. Larger clinical studies are warranted to explore further the exposure-efficacy response relationship at 200 µg/kg and higher ivermectin doses in adults and children.

Ivermectin is a widely used drug for the treatment of helminthiasis and filariasis worldwide, and it has also shown promise for malaria elimination through its potent mosquito-lethal activity. The objective of this study was to develop and validate a high-throughput and sensitive method to quantify ivermectin in plasma and whole blood samples, using automated sample extraction followed by liquid chromatography-tandem mass spectrometry (LC-MS/MS).

Phospholipids were removed in patient whole blood (100 µl) and plasma (100 µl) samples using a 96-well plate Hybrid-solid phase extraction technique. Ivermectin and its isotope-labelled internal standard (ivermectin-D2) were separated on an Agilent Poroshell 120 EC-C18 50mm × 3.0mm I.D. 2.7µm, using a mobile phase of acetonitrile: ammonium formate 2 mM containing 0.5% formic acid (90: 10, v/v). Detection was performed using a triple quadrupole mass spectrometer in the positive ionization mode.

The method was validated in the concentration range 0.970 - 384 ng/ml in both plasma and whole blood matrices. Intra- and inter-batch precisions during the validation were below 15%. There was no carryover or matrix effects detected. Ivermectin is a stable compound and results showed no degradation in the different stability tests.

The validated method proved to have high sensitivity and precision, good selectivity and to be suitable for clinical application or laboratory quantification of ivermectin in plasma or whole blood samples.

Ivermectin is a broad-spectrum anthelmintic used to control onchocerciasis from nematode parasites. As an anthelmintic, ivermectin is designed to have high levels in the gastrointestinal tract, so that the systemic intake is relatively low. Due to the very small concentration of ivermectin, a selective and sensitive approach is needed for the analysis of ivermectin in blood. Several methods have been developed using plasma and Dried Blood Spots, but there are still shortcomings due to hematocrit effects. Therefore, this study was conducted to establish a validated ivermectin analysis method with doramectin as the internal standard in using Ultra High-Performance Liquid Chromatography-Tandem Mass Spectrometry.

Mass spectrometry equipped with triple quadrupole and positive electrospray ionization mode was used to conduct the analysis. For the biological matrix, whole blood was used by Volumetric Absorptive Microsampling and extracted using a protein precipitation technique with a combination of acetonitrile and methanol (1:1). VAMS has some advantages such as not being affected by hematocrit, requires a small and fixed volume of sample, also a more efficient sampling process.

The optimum conditions were achieved with an Acquity® UPLC BEH C18 column (1,7 μm; 2.1 × 100 mm); extracted-flow rate was 0,2 mL/min; mobile phase was 5 mM ammonium formate pH 3.00 and acetonitrile (10:90) with isocratic elution. Multiple Reaction Monitoring (MRM) detection by m/z values was 892.41 > 569.5 for ivermectin and 916,41 > 331,35 for doramectin.

The method has been appropriately validated in compliance with the 2018 guidelines laid out by the US Food and Drug Administration. Resulting the minimum detection (LLOQ) was 1 ng/mL with a linear concentration range spanning from 1 to 150 ng/mL.

Ivermectin and moxidectin, two macrocyclic lactones, are potent antiparasitic drugs currently registered and mainly used against filarial diseases; however, their potential value for improved soil-transmitted helminth (STH) control has been acknowledged. This review provides insights on recent studies evaluating the efficacy of ivermectin and moxidectin as single or coadministered therapy against human soil-transmitted helminthiases (including Strongyloides stercoralis infections) and on pharmacokinetic/pharmacodynamic parameters measured in treated populations. Furthermore, we discuss current gaps for research, highlight advantages - but also existing challenges - for uptake of ivermectin and/or moxidectin treatment schemes into routine STH control in endemic countries.

Although single-dose ivermectin has been widely used in mass-drug administration programs for onchocerciasis and lymphatic filariasis for many years, ivermectin may have utility as an endectocide with mosquito-lethal effects at dosages greater and longer than those used to treat helminths. The final physiologically-based pharmacokinetic (PBPK) model for ivermectin described here was able to capture, with reasonable accuracy, observed plasma drug concentration-time profiles and exposures of ivermectin after a single oral dose of the drug in healthy male (dose range 6-30 mg) and female subjects, in both fasted and fed states, in African patients with onchocerciasis (150 μg/kg) and in African children. The PBPK model can be used for further work on lactation, pediatric dosing (considering CYP3A4 and Pg-p ontogenies), and pregnancy, especially if nonstandard doses will be used. The key findings of our study indicate that absorption of ivermectin may be highly dependent on bile micelle-mediated solubility. The drug is highly lipophilic and permeable, and its plasma exposure appears to be associated with the body mass index of an individual. These are all factors that need to be considered when extrapolating to more complex oral formulations or alternative routes of administration. Administering lower doses over a longer period may attenuate the dependence on bile micelle-mediated solubility. With relevant inputs, the verified PBPK model developed here could be used to simulate plasma exposures following administration of ivermectin by complex generics in development.

Background: Infections with soil-transmitted helminths (STHs) predominantly affect impoverished populations in tropical environments. The periodic administration of single dose benzimidazoles (i.e., albendazole, mebendazole) to at-risk individuals in endemic regions is at the center of STH control strategies. Given the low efficacy of these drugs against trichuriasis, investigation of drug combinations including moxidectin and ivermectin has recently been initiated, yet the identification of the best treatment option requires more research. We present the protocol for a trial investigating the efficacy and safety of co-administered moxidectin and albendazole compared to co-administered ivermectin and albendazole against Trichuris trichiura. Methods: We will conduct a randomized controlled trial enrolling 540 T. trichiura-infected adolescents aged 12-19 years on Pemba Island (Tanzania). The trial will be open-label with blinded outcome assessors. The primary objective is to demonstrate non-inferiority of orally co-administered single-dose moxidectin (8 mg)/albendazole (400 mg) compared to orally co-administered single-dose ivermectin (200 µg/kg)/albendazole (400 mg) in terms of egg reduction rates (ERRs) against T. trichiura infections assessed by Kato-Katz at 14-21 days post-treatment. Secondary objectives include the assessment of the drug combinations' superiority compared to their respective monotherapies, of the cure rates (CRs) against T. trichiura, and the safety and tolerability of all treatments, as well as CRs and ERRs against concomitant STH infections ( Ascaris lumbricoides and hookworm). Potential effects of the treatment regimens on follow-up prevalences of STH at 5-6 weeks and 3 months post-treatment and pharmacokinetic/  pharmacodynamic parameters will also be assessed. Conclusions: Results from this trial will help to inform decision- and policymakers on which anthelminthic combination therapy might improve existing deworming programs and provide a valuable adjunct tool for interrupting STH transmission. Clinicaltrials.gov registration: NCT04700423 (07/01/2021).

A reversed-phase high-performance liquid chromatography (RP-HPLC) method has been developed and validated for the identification and assay of Ivermectin, including the identification and estimation of its process-related impurities and degradation products in bulk drug substance of Ivermectin. Analytes were separated on a HALO C18 column (100 mm × 4.6 mm I.D., 2.7 μm particle size) maintained at 40 °C (column temperature) with gradient elution. All analytes of interests were adequately separated within 25 min. All degradation products, process-related impurities and assay were monitored by ultraviolet detection at 254 nm. The new HPLC method described here successfully separated an isomer peak of the active pharmaceutical ingredient (API) from the major API peak. This newly separated isomer peak is around 1.2 to 1.5% (peak area) in typical API samples, and coelutes with the major API peak by all current HPLC methods. Quantitation limit of the HPLC method is 0.1% of target analytical concentration (~1.0 μg/mL). This method has been demonstrated to be accurate, robust, significantly higher degree of selectivity compared to the HPLC methods of Ivermectin drug substance reported in the literature and in the compendial HPLC methods prescribed in the current USA and European Pharmacopeia.

Background: Infections with soil-transmitted helminths (STHs) predominantly affect impoverished populations in tropical environments. The periodic administration of single dose benzimidazoles (i.e., albendazole, mebendazole) to at-risk individuals in endemic regions is at the center of STH control strategies. Given the low efficacy of these drugs against trichuriasis, investigation of drug combinations including moxidectin and ivermectin has recently been initiated, yet the identification of the best treatment option requires more research. We present the protocol for a trial investigating the efficacy and safety of co-administered moxidectin and albendazole compared to co-administered ivermectin and albendazole against Trichuris trichiura. Methods: We will conduct a randomized controlled trial enrolling 540 T. trichiura-infected adolescents aged 12-19 years on Pemba Island (Tanzania). The primary objective is to demonstrate non-inferiority of orally co-administered single-dose moxidectin (8 mg)/albendazole (400 mg) compared to orally co-administered single-dose ivermectin (200 µg/kg)/albendazole (400 mg) in terms of egg reduction rates (ERRs) against T. trichiura infections assessed by Kato-Katz at 14-21 days post-treatment. Secondary objectives include the assessment of the drug combinations' superiority compared to their respective monotherapies, of the cure rates (CRs) against T. trichiura, and the safety and tolerability of all treatments, as well as CRs and ERRs against concomitant STH infections ( Ascaris lumbricoides and hookworm). Potential effects of the treatment regimens on follow-up prevalences of STH at 5-6 weeks and 3 months post-treatment, infection status derived by quantitative polymerase chain reaction (qPCR), and pharmacokinetic/  pharmacodynamic parameters will also be assessed. Furthermore, a subsample of stool specimens will be analyzed by an updated version of the FECPAK G2 platform. Conclusions: Results from this trial will help to inform decision- and policymakers on which anthelminthic combination therapy might improve existing deworming programs and provide a valuable adjunct tool for interrupting STH transmission. Clinicaltrials.gov registration: NCT04700423 (07/01/2021).

A combination treatment comprising ivermectin (IVM), albendazole (ABZ) and doxycycline (DOX) is often prescribed for lymphatic filariasis patients. Nevertheless, there has not been an analytical method established and documented to determine these compounds simultaneously. Herein, we report a new high-performance liquid chromatographic method coupled with a UV detector (HPLC-UV) to quantify these drugs in plasma and organs. This developed analytical method was validated according to the International Conference on Harmonization (ICH) and US Food and Drug Administration (FDA) guidelines. The validated method was successfully employed to analyze IVM, ABZ along with its metabolites (albendazole sulfoxide (ABZ-OX) and albendazole sulfone (ABZ-ON)), and DOX in the plasma and organs of Wistar rats after simultaneous oral administration. An Xselect CSH™ C₁₈ HPLC column was utilized as a stationary phase, with a mobile phase consisting of 0.1% v/v trifluoracetic acid in water and acetonitrile with a run time of 20 min. The calibration curves in biological samples were found to be linear across the concentration range of 0.01-5 μg mL^-1 for IVM, ABZ and ABZ metabolites, and 0.025-10 μg mL^-1 for DOX with an R value ≥0.998 in each case. The validated method was found to be selective, precise and accurate. Finally, the method developed in this study was deployed to assess the pharmacokinetic profiles and biodistribution of the combination of drugs after oral administration to Wistar rats. The validated HPLC-UV method in this study provides an extensive range of prospective applications for pharmacokinetic-based studies, therapeutic drug monitoring and toxicology.

Avermectins are a group of drugs that occurs naturally as a product of fermenting Streptomyces avermitilis, an actinomycetes, isolated from the soil. Eight different structures, including ivermectin, abamectin, doramectin, eprinomectin, moxidectin, and selamectin, were isolated and divided into four major components (A1a, A2a, B1a and B2a) and four minor components (A1b, A2b, B1b, and B2b). Avermectins are generally used as a pesticide for the treatment of pests and parasitic worms as a result of their anthelmintic and insecticidal properties. Additionally, they possess anticancer, anti-diabetic, antiviral, antifungal, and are used for treatment of several metabolic disorders. Avermectin generally works by preventing the transmission of electrical impulse in the muscle and nerves of invertebrates, by amplifying the glutamate effects on the invertebrates-specific gated chloride channel. Avermectin has unwanted effects or reactions, especially when administered indiscriminately, which include respiratory failure, hypotension, and coma. The current review examines the mechanism of actions, biosynthesis, safety, pharmacokinetics, biological toxicity and activities of avermectins.

Yearly, millions of children are treated globally with ivermectin mainly for neglected tropical diseases. Anatomical, physiological and biochemical differences between children and adults may result in changes in pharmacokinetics. However, paediatric pharmacokinetic data of ivermectin are lacking.

In the framework of a randomized controlled dose-finding trial in rural Côte d'Ivoire, Trichuris trichiura-infected pre-school-aged children (PSAC, 2-5 years) and school-aged children (SAC, 6-12 years) were assigned to 100 or 200 μg/kg and 200, 400 or 600 μg/kg ivermectin, respectively (ISRCTN registry no. ISRCTN15871729). Capillary blood was collected on dried blood spot cards until 72 h post-treatment. Ivermectin was quantified by LC-MS/MS, and pharmacokinetic parameters were evaluated by non-compartmental analysis.

C max and AUC increased in PSAC and SAC with ascending doses and were similar in both age groups when the current standard dose (200 μg/kg) was administered (∼23 ng/mL and ∼350 ng×h/mL, respectively). PSAC with lower BMI were associated with significantly higher AUCs. AUC and Cmax were ∼2-fold lower in children compared with parameters previously studied in adults, whereas body weight-adjusted CL/F (∼0.35 L/h/kg) was significantly higher in children. Tmax (∼6 h), t1/2 (∼18 h), mean residence time (MRTINF) (∼28 h) and V/F (∼8 L/kg) were similar in all paediatric treatment arms.

A positive association of AUC or Cmax with dose was observed in both age groups. Undernutrition might influence the AUC of ivermectin in PSAC. Ivermectin shows a lower exposure profile in children compared with adults, highlighting the need to establish dosing recommendations for different age groups.

Ivermectin is a commonly used broad-spectrum antiparasitic drug, yet doses that produce consistent exposure coverage across age have not been characterized, and no data are available in children weighing < 15 kg. First, a population pharmacokinetic model is developed based on data from 200 children and 11 adults, treated with 100-600 μg/kg ivermectin. Second, model-based simulations are performed to identify a dosing strategy that achieves equivalent exposure coverage in children and adults. Median (90% confidence interval) clearance of 0.346 (0.12-0.73) L/hour/kg in pre-school-aged (2-5 years) children is similar to 0.352 (0.17-0.69) L/hour/kg in school-aged (6-12 years) children but higher than in adults (0.199 (0.10-0.31) L/hour/kg), resulting in significantly lower exposure in children following a 200 μg/kg dose. Simulations indicate that a dose increase to 300 and 250 μg/kg in children aged 2-5 and 6-12 years, respectively, will achieve equivalent ivermectin exposure coverage in children and adults.

Soil-transmitted helminth (STH) infections still remain a major health problem in poor rural settings. The lack of efficacious drugs against all STH species raises interest in drug combinations. Drug-drug interactions (DDIs) are, however, of major concern, so careful in vitro and in vivo characterization is needed. The combination of tribendimidine with either ivermectin or oxantel pamoate targets a broad range of STHs and thus represents a promising treatment alternative. Drug-drug interactions, however, have not yet been investigated. Therefore, the effects of combinations of ivermectin, oxantel pamoate, and tribendimidine's active metabolite deacylated amidantel (dADT) on cytochrome P450 (CYP450) metabolism were evaluated, followed by a pharmacokinetic analysis of tribendimidine and ivermectin alone and in combination in healthy rats. Oxantel pamoate is only poorly absorbed and was therefore excluded from pharmacokinetic analysis. No evident effect was observed for tribendimidine-oxantel pamoate at the CYP450 metabolism level, whereas a combination of tribendimidine and ivermectin led to moderately increased CYP2D6 inhibition compared to ivermectin or tribendimidine alone. Coadministration of tribendimidine with ivermectin altered neither the time to maximum concentration of drug in plasma (T _max) nor the elimination half-lives of dADT, the acetylated derivative of amidantel (adADT), and ivermectin. While the area under the concentration-versus-time curve (AUC) and maximum concentration of drug in plasma (C _max) values of dADT, adADT, and ivermectin are reduced by coadministration, the change is insufficient to declare that a DDI has been detected. Further studies are necessary to understand the observed interaction of tribendimidine and ivermectin, which is not related to P450 metabolism, and its significance for the situation in humans.