Pharmacokinetic profile and anthelmintic efficacy of moxidectin administered by different doses and routes to feedlot calves

Fazzio, Luis Emilio; Moreno, Laura; Galván, Walter Rubén; Cantón, Candela; Álvarez, Luis Ignacio Ortega; Streitenberger, Nicolás; Sánchez, Ricardo Ortíz; Lanusse, Carlos; Sanabria, Rodrigo Eduardo Fabrizio

doi:10.1016/j.vetpar.2018.12.016

Cited by 9 publications

(7 citation statements)

References 42 publications

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“…Table shows the main PK parameters of four studies published, following an oral administration of different doses of moxidectin in different large animals, and preclinical data in uninfected rats, obtained from drug approval documents for the treatment of human onchocerciasis . Of note, several other studies investigated the PK parameters of moxidectin using different formulations and other routes of administrations. − Additionally, our study evaluated PK parameters in blood sampled with the Mitra®® sampling device, while the compared studies worked with plasma. This method difference, however, should not significantly influence the results, as shown by a recent study comparing Mitra®® with plasma sampling …”

Section: Results and Discussionmentioning

confidence: 99%

Characterization of Moxidectin against Strongyloides ratti: In Vitro and In Vivo Activity and Pharmacokinetics in the Rat Model

et al. 2020

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Strongyloides stercoralis is a soil-transmitted helminth affecting an estimated 30−100 million people. Since the infection may be severe and life-threatening, accessible and effective treatment is pivotal. Currently, ivermectin is the drug of choice but has limitations. Moxidectin, a veterinary anthelminthic approved for use in human onchocerciasis, is a promising drug alternative against strongyloidiasis. In this study, we evaluated the in vitro activity of moxidectin on Strongyloides ratti larvae (L 3 ) and adult females and the activity as well as the pharmacokinetics of moxidectin in S. ratti infected rats. In vitro, moxidectin had an activity that was similar to that of ivermectin, with median lethal concentration values for L 3 and adults in the range of 0.08− 1.44 μM, after 72 h of exposure. In vivo, doses of 250, 500, and 750 μg/kg of moxidectin resulted in a reduction of the worm burden ranging from 48.5 to 75%. At the highest dose (750 μg/kg) we observed a maximal blood concentration of 50.3 ng/mL and an area under the curve of 895.2 ng × h/mL. The half-life in rats was 9 h, and moxidectin was cleared to undetectable blood levels within 7 d (<10 ng/mL). No exposure-response relationship was observed. This work contributes to the characterization of moxidectin in the treatment of S. ratti as a model of Strongyloides spp. and, as such, supports moving moxidectin further along the drug development pipeline in the treatment of human strongyloidiasis.

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Section: Results and Discussionmentioning

confidence: 99%

Characterization of Moxidectin against Strongyloides ratti: In Vitro and In Vivo Activity and Pharmacokinetics in the Rat Model

et al. 2020

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“…Therefore, consistent with the observations of Old et al (2021) and other studies (e.g., Martin et al 2019), successful treatment of mange in bare-nosed wombats with moxidectin requires multiple treatments over many weeks. Importantly, the data from Death et al (2011) and pharmacokinetic studies in other animals (Fazzio et al 2019) show that higher plasma concentrations or administering higher subcutaneous doses did not change the elimination dynamics of moxidectin, suggesting that increasing dose volumes within therapeutic limits will not extend the duration of therapeutic coverage and will not prevent reinfestation.…”

Section: Pharmacokinetics Of Moxidectin In Wombatsmentioning

confidence: 98%

Drug dose and animal welfare: important considerations in the treatment of wildlife

et al. 2022

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A recent publication in Parasitology Research by (Old et al. Parasitol Res 120:1077-1090 raises the topical and often controversial issue of the treatment of wildlife by personnel with little or no formal scientific training (e.g. wildlife carers). In a valuable contribution to the subject, Old and colleagues document a wide range of topical (pour-on) application doses and frequencies of moxidectin (Cydectin®) administered in situ to bare-nosed wombats (Vombatus ursinus) by members of the wildlife carer/treater community in southeast Australia to treat sarcoptic mange disease. This treatment occurred under minor use permits issued by the Australian Pesticides and Veterinary Management Authority (APVMA). These permits do not require veterinary supervision, although carers are registered and are expected to comply with the guidelines of this permit. The prevalence and severity of sarcoptic mange in wildlife is influenced by a variety of factors including mite biology, environmental conditions, population density, animal behaviour and immune susceptibility (Browne et al. Bioscience, 2021). In bare-nosed wombats, combinations of these elements play a substantial role in making the treatment of an already difficult disease more complex. (Moroni et al. Parasit Vectors 13:471, 2020) comment that any pharmacological treatment of freeranging wildlife must consider these factors when assessing their feasibility and implications, especially in the context of emerging drug resistance and potential long-term ecological impacts. As individuals with significant interest in sarcoptic mange and representing a range of professional research and veterinary expertise, we see value in providing expert commentary on this issue.

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“…With specific regard to MOX, similar results have been obtained for routes of administration that lead to different exposure profiles and thus different efficacy in cattle (Leathwick and Miller, 2013; Fazzio et al, 2019), and higher doses delivered to the site of infection are effective against ML-resistant parasites in sheep (Lloberas et al, 2015). It is important to consider the exposure profile as a composite of both maximum concentration and duration of exposure to effective concentrations.…”

Section: Attributes Of Moxidectin That May Reduce Selection For Resismentioning

confidence: 58%

“…It is also clearly evident in the macrofilaricidal action of flubendazole, for which prolonged exposure to low concentrations in vivo is much more effective than shorter exposures to high concentrations (Mackenzie and Geary, 2011; Geary et al, 2019). These findings form the basis of a more rational choice of dosing regimens to enhance efficacy of MLs, including MOX, and other anthelmintics (Lanusse and Prichard, 1993; Lloberas et al, 2012b; Lanusse et al, 2014, 2018, 2016; Leathwick and Luo, 2017; Lifschitz et al, 2017; Fazzio et al, 2019) based on increasing either the intensity of exposure to the anthelmintic at the site of infection, or the duration of exposure, although neither manipulation is uniformly able to fully overcome AR and may vary with different MLs.…”

Section: Attributes Of Moxidectin That May Reduce Selection For Resismentioning

confidence: 97%

Perspectives on the utility of moxidectin for the control of parasitic nematodes in the face of developing anthelmintic resistance

Prichard

Geary

2019

International Journal for Parasitology: Drugs and Drug Resistan

108

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Macrocyclic lactone (ML) anthelmintics are the most important class of anthelmintics because of our high dependence on them for the control of nematode parasites and some ectoparasites in livestock, companion animals and in humans. However, resistance to MLs is of increasing concern. Resistance is commonplace throughout the world in nematode parasites of small ruminants and is of increasing concern in horses, cattle, dogs and other animals. It is suspected in Onchocerca volvulus in humans. In most animals, resistance first arose to the avermectins, such as ivermectin (IVM), and subsequently to moxidectin (MOX). Usually when parasite populations are ML-resistant, MOX is more effective than avermectins. MOX may have higher intrinsic potency against some parasites, especially filarial nematodes, than the avermectins. However, it clearly has a significantly different pharmacokinetic profile. It is highly distributed to lipid tissues, less likely to be removed by ABC efflux transporters, is poorly metabolized and has a long half-life. This results in effective concentrations persisting for longer in target hosts. It also has a high safety index. Limited data suggest that anthelmintic resistance may be overcome, at least temporarily, if a high concentration can be maintained at the site of the parasites for a prolonged period of time. Because of the properties of MOX, there are reasonable prospects that strains of parasites that are resistant to avermectins at currently recommended doses will be controlled by MOX if it can be administered at sufficiently high doses and in formulations that enhance its persistence in the host. This review examines the properties of MOX that support this contention and compares them with the properties of other MLs. The case for using MOX to better control ML-resistant parasites is summarised and some outstanding research questions are presented.

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Pharmacokinetic profile and anthelmintic efficacy of moxidectin administered by different doses and routes to feedlot calves

Cited by 9 publications

References 42 publications

Characterization of Moxidectin against Strongyloides ratti: In Vitro and In Vivo Activity and Pharmacokinetics in the Rat Model

Characterization of Moxidectin against Strongyloides ratti: In Vitro and In Vivo Activity and Pharmacokinetics in the Rat Model

Drug dose and animal welfare: important considerations in the treatment of wildlife

Perspectives on the utility of moxidectin for the control of parasitic nematodes in the face of developing anthelmintic resistance

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