Fexofenadine in horses: pharmacokinetics, pharmacodynamics and effect of ivermectin pretreatment

The pharmacokinetics and the effects on inhibition of histamine-induced cutaneous wheal formation of the histamine H1-antagonist fexofenadine were studied in horse. The effect of ivermectin pretreatment on the pharmacokinetics of fexofenadine was also examined. After intravenous infusion of fexofenadine at 0.7 mg/kg bw the mean terminal half-life was 2.4 h (range: 2.0-2.7 h), the apparent volume of distribution 0.8 L/kg (0.5-0.9 L/kg), and the total body clearance 0.8 L/h/kg (0.6-1.2 L/h/kg). After oral administration of fexofenadine at 10 mg/kg bw bioavailability was 2.6% (1.9-2.9%). Ivermectin pretreatment (0.2 mg/kg, p.o.) 12 h before oral fexofenadine decreased the bioavailability to 1.5% (1.4-2.1%). In addition, the area under the plasma concentration-time curve decreased 27%. Ivermectin did not affect the pharmacokinetics of i.v. administered fexofenadine. Ivermectin may influence fexofenadine absorption by interfering in intestinal efflux and influx pumps, such as P-glycoprotein and the organic anion transport polypeptide family. Oral and i.v. fexofenadine significantly decreased histamine-induced wheal formation, with a maximal duration of 6 h. A pharmacokinetic/pharmacodynamic link model indicated that fexofenadine in horse has antihistaminic effects at low plasma concentrations (EC50 = 16 ng/mL). However, oral treatments of horses with fexofenadine may not be suitable due to the low bioavailability.     

Cetirizine in horses: pharmacokinetics and pharmacodynamics following repeated oral administration

The pharmacokinetics of the histamine H(1)-antagonist cetirizine and its effect on histamine-induced cutaneous wheal formation were studied in six healthy horses following repeated oral administration. After three consecutive administrations of cetirizine (0.2 mg/kg body weight, bw) every 12h, the trough plasma concentration of cetirizine was 16+/-4 ng/mL (mean+/-SD) and the wheal formation was inhibited by 45+/-23%. After four additional administrations of cetirizine (0.4 mg/kg bw) every 12 h, the trough plasma concentration was 48+/-15 ng/mL and the wheal formation was inhibited by 68+/-11%. The terminal half-life was about 5.8 h. A pharmacokinetic/pharmacodynamic link model showed that the maximal inhibition of wheal formation was about 95% and the EC(50) about 18 ng/mL. It is concluded that cetirizine in doses of 0.2-0.4 mg/kg bw administered at 12 h intervals exhibits favourable pharmacokinetic and pharmacodynamic properties without causing visible side effects, and the drug may therefore be a useful antihistamine in equine medicine.     

The pharmacokinetics and antiparasitic activity of ivermectin in Hutsul and Toric horses

The aim of this study was to compare the pharmacokinetics of ivermectin and its antiparasitic activity in two horse breeds. Eight Hutsul and 14 Toric horses were administered ivermectin orally at a dose of 0.2 mg/kg body weight. Blood samples were collected for 96 hr, and faecal samples were collected one day before and on days 14 and 21 after drug administration. Ivermectin concentrations in plasma samples were determined by high‐performance liquid chromatography. Ivermectin concentration was significantly higher in Toric than in Hutsul horses 90 min after ivermectin administration and was maintained at higher level for up to 96 hr. The area under the concentration versus the time curve from 0 to the last sampling point (AUC_0→t) and the maximum plasma concentration (C_max) were significantly higher in Toric than in Hutsul horses (1792.09 ± 246.22 μg × hr/L vs. 716.99 ± 255.81 μg × hr/L and 62.72 ± 17.97 ng/ml vs. 35.34 ± 13.61 ng/ml, respectively). No parasitic eggs were found in the faecal samples collected from both groups of horses on days 14 and 21 after drug administration. The obtained results indicate that although the pharmacokinetics of ivermectin may differ significantly between horse breeds, these differences do not affect the effectiveness of therapy.     

Plasma pharmacokinetics and faecal excretion of ivermectin, doramectin and moxidectin following oral administration in horses

The present study was carried out to investigate whether the pharmacokinetics of avermectins or a milbemycin could explain their known or predicted efficacy in the horse. The avermectins, ivermectin (IVM) and doramectin (DRM), and the milbemycin, moxidectin (MXD), were each administered orally to horses at 200 microg/kg bwt. Blood and faecal samples were collected at predetermined times over 80 days (197 days for MXD) and 30 days, respectively, and plasma pharmacokinetics and faecal excretion determined. Maximum plasma concentrations (Cmax) (IVM: 21.4 ng/ml; DRM: 21.3 ng/ml; MXD: 30.1 ng/ml) were obtained at (tmax) 7.9 h (IVM), 8 h (DRM) and 7.9 h (MXD). The area under the concentration time curve (AUC) of MXD (92.8 ng x day/ml) was significantly larger than that of IVM (46.1 ng x day/ml) but not of DRM (53.3 ng x day/ml) and mean residence time of MXD (17.5 days) was significantly longer than that of either avermectin, while that of DRM (3 days) was significantly longer than that of IVM (2:3 days). The highest (dry weight) faecal concentrations (IVM: 19.5 microg/g; DRM: 20.5 microg/g; MXD: 16.6 microg/g) were detected at 24 h for all molecules and each compound was detected (> or = 0.05 microg/g) in faeces between 8 h and 8 days following administration. The avermectins and milbemycin with longer residence times may have extended prophylactic activity in horses and may be more effective against emerging and maturing cyathostomes during therapy. This will be dependent upon the relative potency of the drugs and should be confirmed in efficacy studies.     

Comparison of the pharmacokinetics of moxidectin (Equest®) and ivermectin (Eqvalan®) in horses

A study was undertaken in order to evaluate and compare plasma disposition kinetic parameters of moxidectin and ivermectin after oral administration of their commercially available preparations in horses. Ten clinically healthy adult horses, weighing 390-446 kg body weight (b.w.), were allocated to two experimental groups of five horses. Group I was treated with an oral gel formulation of moxidectin (MXD) at the manufacturers recommended therapeutic dose of 0.4 mg/kg bw. Group II was treated with an oral paste formulation of ivermectin (IVM) at the manufacturers recommended dose of 0.2 mg/kg b.w. Blood samples were collected by jugular puncture at different times between 0.5 h and 75 days post-treatment. After plasma extraction and derivatization, samples were analysed by HPLC with fluorescence detection. Computerized kinetic analysis was carried out. The parent molecules were detected in plasma between 30 min and either 30 (IVM) or 75 (MXD) days post-treatment. Both drugs showed similar patterns of absorption and no significant difference was found for the time corresponding to peak plasma concentrations or for absorption half-life. Peak plasma concentrations (Cmax) of 70.3+/-10.7 ng/mL (mean +/- SD) were obtained for MXD and 44.0+/-23.1 ng/mL for IVM. Moreover, the values for area under concentration-time curve (AUC) were 363.6+/-66.0 ng x d/mL for the MXD treated group, and 132.7+/-47.3 ng x d/mL for the IVM treated group. The mean plasma residence times (MRT) were 18.4+/-4.4 and 4.8+/-0.6 days for MXD and IVM treated groups, respectively. The results showed a more prolonged residence of MXD in horses as demonstrated by a four-fold longer MRT than for IVM. The longer residence and the higher concentrations found for MXD in comparison to IVM could possibly explain a more prolonged anthelmintic effect. It is concluded that in horses the commercial preparation of MXD presents a pharmacokinetic profile which differs significantly from that found for a commercial preparation of IVM. To some extent these results likely reflect differences in formulation and doses.     

The antiparasitic activity of ivermectin in horses

Parenteral administration of ivermectin (22,23-dihydroavermectin B₁) significantly reduced the numbers of adult large and small strongyles, the immature stages of small strongyles, pinworm and ascarid, the microfilariae of Onchocerca cervicalis and gastrophilid bots from naturally infected horses. Strongylus vulgaris, S. edentatus and S. equinus were effectively removed by 0.02 mg/kg. Adult small strongyles, Cyathostomum pateratum, C. catinatum, Cylicocyclus nassatus, C. leptostomus, Cyliostephanus minutus, C. longibursatus and C. goldi, were effectively removed by 0.1 mg/kg. Fourth stage small strongyles (cyathostomes), 4th stage Oxyuris equi, 5th stage Parascaris equorum and the microfilarie of Onchocerca cervicalis were significantly reduced by 0.1 mg/kg also. The stomach bots, Gastrophilus intestinalis and G. nasalis, were effectively removed by 0.02 mg of ivermectin/kg. Analysis of the dose response curves obtained for the nematode and larval dipteran parasites found in these naturally infected horses suggests that a parenteral dose of 0.2 mg/kg ivermectin would produce 95% or more removal of these parasites. The antiparasitic efficacies observed for ivermectin in this controlled trial were equivalent to the efficacies found in an abbreviated critical trial contained within the controlled trial. However, it was calculated that the man—day effort required for data collection from one critical trial horse was the same as for 6 controlled-trial horses.     

Searching for ivermectin resistance in Dutch horses

A study was conducted to evaluate the occurrence of resistance against, in particular, ivermectin in cyathostomins in the Netherlands. Seventy horse farms were visited between October 2007 and November 2009. In initial screening, faecal samples were collected 2 weeks after deworming with either ivermectin, moxidectin or doramectin. Pooled faecal samples from a maximum of 10 horses were examined for worm eggs using a modified McMaster technique and for worm larvae after faecal larval cultures. In total 931 horses were involved. On 15 of 70 farms eggs and/or larvae were found. On 8 of these 15 farms a FECRT with ivermectin was performed on 43 horses. Efficacy of ivermectin against cyathostomins of 93% was found in one animal on one farm. Additionally, the strategies and efforts of the horse owners to control cyathostomins, as well as risk factors for the development of macrocyclic lactone resistance were evaluated with a questionnaire. Strikingly, many responders indicated that the control of cyathostomins in horses is achieved through very frequent deworming. Fourteen percent of these owners deworm seven times per year or more. On 34% of the 70 farms treatment was repeated within the Egg Reappearance Period of a product.     

Alternative antiparasitic treatment of horses with pyrantel pamoate suspension and ivermectin oral solution compared with horses treated only with ivermectin

A practical parasite control program was evaluated in a 2-year clinical trial using pyrantel pamoate suspension (PYR) and ivermectin oral solution (IVM) in a seasonal rotation program, in comparison with continued use of IVM given at 2-month intervals. At least 15 horses in each of 2 treatment groups were distributed over 8 locations. In the alternation program, IVM was given twice (October, December) during the botfly (Gasterophilus spp.) season and again in April to treat against the lighter botfly season and to kill existing Onchocerca microfilariae prior to heavy Culicoides swarming. Pyrantel was given in February, June and August to continue suppression of strongyle infections and to treat against potentially developing Anoplocephala infections. In the program of IVM continuous use, the drug was given on the same schedule as either treatment on the alternation program.The course of strongyle infections was monitored by fecal sample analyses (EPG) at semimonthly intervals and by larval cultures of treatment pairs prepared at each treatment interval (alternation program) or at 4-month intervals (continuous IVM program). The strongyle egg count numbers were reduced to zero by the first IVM treatment, increased only slightly by the next treatment at 2 months, and repeated the reduced pattern with each treatment for 2 years. The alternation program in the first year had typical responses to each drug: IVM reducing strongyle EPG counts to zero which increased slightly at 2 months, followed by the PYR treatment, which reduced the strongyle egg counts for 4 weeks with rebound at 6 and 8 weeks. At the end of the first year and into the second, the IVM treatments of October and December established a zero or low strongyle EPG pattern which continued through the spring with PYR and IVM treatments. The second summer PYR treatments then maintained far better cyathostome control than had been reported for this drug. There may be a complementary or enhancing effect by prior treatment with ivermectin within the rotation protocol. The practical therapeutic compatibility between these 2 antiparasitics became obvious. Anoplocephala eggs were found in feces of some horses treated with IVM only, but no Anoplocephala eggs were found in post-treatment feces of horses treated on the alternation program.Strongyle larval cultures prepared as treatment pairs indicated high efficacy by ivermectin throughout the 2 years whether used alone or as a rotational drug, with improved cyathostome control by pyrantel pamoate. The combined use of EPG determinations and concurrent larval cultures in anthelmintic evaluations provide a greater spectrum of reliable results than from parasite egg counts alone.     

Pharmacokinetics of doramectin and ivermectin after oral administration in horses

A study was undertaken in order to compare plasma disposition kinetic parameters of doramectin (DRM) and ivermectin (IVM) in horses after oral administration. Ten crossbreed adult horses, clinically healthy, weighing 380-470 kg body weight (bw) were selected for study. Faecal examinations were performed to determine faecal parasite egg counts. Horses were allocated to two groups of five animals to provide an even distribution considering the variables sex, body weight and faecal egg count. Group I, were treated with an oral paste formulation of IVM at 0.2 mg/kg b/w and Group II, were treated with an oral dose of 0.2 mg/kg bw of DRM prepared as paste from the injectable formulation for oral administration. Blood samples were collected by jugular puncture between 0 h and 75 days post-treatment. Plasma was separated and later solid phase extraction and derivatization samples were analysed by high performance liquid chromatography (HPLC); a computerised kinetic analysis was carried out. Data were compared using the Mann-Whitney U-test.The mean plasma concentrations of DRM and IVM after oral administration in horses were detected until 30 and 20 days, respectively. Both drugs showed similar patterns of absorption and no significant differences were found for peak concentration, the time to peak concentration, or for absorptive half-life. The terminal elimination half-life was significantly (P<0.05) longer in the DRM treated group than for the IVM treated group. The differences observed in the elimination half-life explain the longer mean residence time and high values of area under the concentration time curve for the group treated with DRM, which are 30% higher than those of the IVM group. Considering its pharmacokinetics, tolerance and anthelmintic efficacy, the oral administration of DRM, could be an alternative to IVM for the control of parasitic diseases of horses.     

Detection and pharmacokinetics of tetrahydrogestrinone in horses

The anti-doping rules of national and international sport federations ban any use of tetrahydrogestrinone (THG) in human as well as in horse sports. Initiated by the THG doping scandals in human sports a method for the detection of 3-keto-4,9,11-triene steroids in horse blood and urine was developed. The method comprises the isolation of the analytes by a combination of solid phase and liquid–liquid extraction after hydrolysis and solvolysis of the steroid conjugates. The concentrations of THG in blood and urine samples were measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS).
A THG excretion study on horses was conducted to verify the method capability for the analysis of postadministration urine samples. In addition, blood samples were collected to allow for determination of the pharmacokinetics of THG in horses. Following the administration of a single oral dose of 25 μg THG per kg bodyweight to 10 horses, samples were collected at appropriate intervals. The plasma levels of THG reached maximal concentrations of 1.5–4.8 ng/mL. Twenty-four hours after the administration plasma levels returned to baseline. In urine, THG was detectable for 36 h. Urinary peak concentrations of total THG ranged from 16 to 206 ng/mL. For the 10 horses tested, the mean plasma clearance of THG was 2250 mL/h/kg and the plasma elimination half-life was 1.9 h.     

Population pharmacokinetics of marbofloxacin in horses: preliminary analysis

Population pharmacokinetic of marbofloxacin was investigated on 21 healthy and 16 diseased horses to assess interindividual variability of drug exposure. Demographic, physiologic and disease covariables were tested using mixed effects models. As a preliminary analysis, this study has demonstrated that none of the tested covariables were significant in regression models for compartmental volumes or clearance of distribution, but the clinical status of the horse (healthy/diseased) was a significant covariable (P < 0.01) for systemic clearance. Clearance had a lower mean and a higher variance for diseased horses than healthy horses, with respectively a mean of 0.209 and 0.284 L/h/kg and a coefficient of variation of 52 and 15%. Consequently, variability of AUC was greater in diseased horses. Considering an AUC/MIC ratio below 60 h as a prediction of poor efficacy, a dosage regimen of 2 mg/kg intravenous was deemed to be inadequate for 19% of diseased horses if the MIC of the bacteria was 0.1 microg/mL. However 93% of diseased horses could achieve a ratio above 125 h, predicting a very good efficacy, for the MIC(90) of Enterobacteriacae (0.027 microg/mL).     

The pharmacokinetics and metabolism of ivermectin in domestic animal species

The pharmacokinetic properties of drugs are closely related to their pharmacological efficacy. The kinetics of ivermectin are characterised, in general terms, by a slow absorption process, a broad distribution in the organism, low metabolism, and slow excretion. The kinetics vary according to the route of administration, formulation, animal species, body condition, age, and physiological status, all of which contribute to differences in drug efficacy. Characterisation of ivermectin kinetics can be used to predict and optimise the value of the parasiticide effects and to design programmes for parasite control. This article reviews the pharmacokinetics of ivermectin in several domestic animal species.     

Alternative antiparasitic treatment of horses with pyrantel pamoate suspension and ivermectin oral solution compared with horses treated only with ivermectin oral solution

A practical parasite control program was evaluated in a 2-year clinical trial using pyrantel pamoate suspension (PYR) and ivermectin oral solution (IVM) in a seasonal rotation program, in comparison with continued use of IVM given at 2-month intervals. At least 15 horses in each of 2 treatment groups were distributed over 8 locations. In the alternation program, IVM was given twice (October, December) during the botfly (Gasterophilus spp.) season and again in April to treat against the lighter botfly season and to kill existing Onchocerca microfilariae prior to heavy Culicoides swarming. Pyrantel was given in February, June and August to continue suppression of strongyle infections and to treat against potentially developing Anoplocephala infections. In the program of IVM continuous use, the drug was given on the same schedule as either treatment on the alternation program.The course of strongyle infections was monitored by fecal sample analyses (EPG) at semimonthly intervals and by larval cultures of treatment pairs prepared at each treatment interval (alternation program) or at 4-month intervals (continuous IVM program). The strongyle egg count numbers were reduced to zero by the first IVM treatment, increased only slightly by the next treatment at 2 months, and repeated the reduced pattern with each treatment for 2 years. The alternation program in the first year had typical responses to each drug: IVM reducing strongyle EPG counts to zero which increased slightly at 2 months, followed by the PYR treatment, which reduced the strongyle egg counts for 4 weeks with rebound at 6 and 8 weeks. At the end of the first year and into the second, the IVM treatments of October and December established a zero or low strongyle EPG pattern which continued through the spring with PYR and IVM treatments. The second summer PYR treatments then maintained far better cyathostome control than had been reported for this drug. There may be a complementary or enhancing effect by prior treatment with ivermectin within the rotation protocol. The practical therapeutic compatibility between these 2 antiparasitics became obvious. Anoplocephala eggs were found in feces of some horses treated with IVM only, but no Anoplocephala eggs were found in post-treatment feces of horses treated on the alternation program.Strongyle larval cultures prepared as treatment pairs indicated high efficacy by ivermectin throughout the 2 years whether used alone or as a rotational drug, with improved cyathostome control by pyrantel pamoate. The combined use of EPG determinations and concurrent larval cultures in anthelmintic evaluations provide a greater spectrum of reliable results than from parasite egg counts alone.     

Antiparasitic activity of an ivermectin and praziquantel combination paste in horses

Modern anthelmintic use in horses has decreased the prevalence of the large strongyles, which has in turn shifted the focus of parasitologists to the pathogenic importance of the small strongyles, tapeworms, and other parasites. These studies show that a combination product containing ivermectin and praziquantel allowed efficacious treatment of horses for nematode, cestode, and bot infections. The use of this combination product may be of special benefit to horses that are mainly kept outdoors and on grazing pastures.