moxidectin and Strongyloidiasis

Moxidectin has recently attracted attention as a novel candidate for the treatment of helminth infections, including Strongyloides stercoralis. This study aims to characterize the population pharmacokinetics (PPK) of moxidectin in S. stercoralis-infected adults using a pharmacometric approach, and to perform model-based simulations to explore different drug dosing strategies.. A PPK study embedded in a dose-escalation phase IIa trial was conducted in NamBak, Laos. Eight micro blood samples were collected from each of 96 S. stercoralis-infected adults following a moxidectin dose-ranging study, from 2 to 12 mg. A PPK model was developed using nonlinear mixed-effects modeling, and dosing strategies were explored using simulations in S. stercoralis-infected subjects with varying age and body weight (n = 5000 per dosing strategy).. A two-compartment model including delayed absorption with lag-time best described the available PK data. Allometric scaling was applied to account for the influence of body weight. High clearance was found in the infected adults (4.47 L/h [95% confidence interval 3.63-5.39] for a 70 kg individual) compared with that previously reported for healthy adults. Model-based simulations indicated similar variability in mean ± standard deviation area under the curve from time zero to infinity of 1907 ± 1552 and 2175 ± 1670 ng × h/mL in the 60-70 kg weight group, after 8 mg fixed- or weight-based dosing, respectively.. We describe the first PPK model for moxidectin in adults with S. stercoralis infection. Equivalent exposures after fixed-dose and weight-dependent dosing strategies support the use of a simple fixed-dose approach, particularly in large-scale treatment programs.. Registered at ClinicalTrials.gov (NCT04056325).

Topics: Adult; Animals; Humans; Macrolides; Strongyloides stercoralis; Strongyloidiasis

Strongyloidiasis represents a major public health issue, particularly in resource-limited countries. Preliminary studies suggest that moxidectin might serve as an alternative to the only available treatment option, ivermectin. We aimed to evaluate the efficacy and safety of ascending doses of moxidectin in Strongyloides stercoralis-infected patients.. We did a randomised, parallel-group, single-blinded, placebo-controlled, dose-ranging, phase 2a trial in four villages in northern Laos. Eligible adults (aged 18-65 years) with S stercoralis infection intensities of at least 0·4 larvae per g of stool in at least two stool samples were randomly assigned (1:1:1:1:1:1:1) by use of computerised, stratified, block randomisation into seven treatment groups: 2 mg of moxidectin, 4 mg of moxidectin, 6 mg of moxidectin, 8 mg of moxidectin, 10 mg of moxidectin, 12 mg of moxidectin, or placebo. Participants and primary outcome assessors were masked to treatment allocation, but study site investigators were not. Participants received a single oral dose of their allocated dose of moxidectin in 2 mg tablets, or four placebo tablets. Three stool samples were collected at baseline and two stool samples were collected 28 days after treatment from each participant. A Baermann assay was used to quantify S stercoralis infection and Kato-Katz thick smears were used to qualitatively identify coinfections with additional helminths species. The primary endpoint was cure rate against S stercoralis and was analysed in an available case analysis set, defined as all randomly assigned participants with primary endpoint data. Predicted cure rates and associated CIs were estimated with hyperbolic E. Between Nov 27, 2019, and March 15, 2020, 785 adults were screened for trial eligibility. Of these, 223 participants were randomly assigned to treatment groups and 209 completed the study and were analysed for the primary outcome. 2 mg of moxidectin had a predicted cure rate of 75% (95% CI 59-87; 22 [73%] of 30 cured) against S stercoralis compared with a predicted cure rate of 14% (5-31; four [14%] of 29 cured) for placebo. With escalating doses, the probability of cure increased from 83% (95% CI 76-88; 26 [90%] of 29 cured) at 4 mg to 86% (79-90; 27 [84%] of 32 cured) at 6 mg, and to 87% (80-92; 24 [83%] of 29 cured) at 8 mg, levelling off at 88% (80-93; 29 [97%] of 30 cured) at 10 mg and 88% (80-93; 26 [87%] of 30 cured) at 12 mg. Moxidectin was well tolerated across all treatment groups, with no serious adverse events being recorded and all reported symptoms being classified as mild.. 4-12 mg of moxidectin showed promising tolerability and efficacy profiles in the treatment of S stercoralis infections in adults. Because 8 mg of moxidectin is used for the treatment of onchocerciasis and has been evaluated for other helminth infections, we recommend this dose for phase 2b and phase 3 trials of strongyloidiasis therapy.. Fondazione Adiuvare.

Topics: Adult; Animals; Anthelmintics; Drug-Related Side Effects and Adverse Reactions; Feces; Female; Humans; Laos; Macrolides; Male; Middle Aged; Single-Blind Method; Strongyloides stercoralis; Strongyloidiasis; Treatment Outcome

Infections with Strongyloides stercoralis are of considerable public health relevance. Moxidectin, a well-established drug in veterinary medicine under consideration for regulatory submission for the treatment of onchocerciasis, might serve as an alternative to the widely used ivermectin.. We conducted an exploratory, randomized, single-blind trial to evaluate the efficacy and safety of moxidectin (8 mg) vs ivermectin (200 μg/kg) against S. stercoralis infections. Cure rate (CR) against S. stercoralis was the primary outcome. Safety and efficacy against coinfections with soil-transmitted helminths and Opisthorchis viverrini were secondary outcomes. Noninferiority required the lower limit of the 95% confidence interval (CI) of the differences in CRs not exceed 7 percentage points.. A total of 127 participants were enrolled and randomly assigned to the 2 treatments whereby 1 participant per arm was lost to follow-up. We observed a CR of 93.7% (59/63) for moxidectin compared to 95.2% (59/62) for ivermectin. Differences between CRs were estimated as -1.5% percentage points (95% CI, -9.6 to 6.5), thus the lower limit of the CI exceeds the noninferiority margin of 7 percentage points. No side effects were observed. CRs against hookworm infection were 57% (moxidectin) and 56% (ivermectin). Low efficacy for both drugs against O. viverrini was observed.. Moxidectin might be a safe and efficacious alternative to ivermectin for the treatment of S. stercoralis infection, given that only slight differences in CRs were observed. However, noninferiority could not be demonstrated. Larger clinical trials should be conducted once the drug is marketed.. Current Controlled Trials: ISRCTN11983645.

Topics: Adult; Animals; Antinematodal Agents; Coinfection; Equivalence Trials as Topic; Female; Humans; Ivermectin; Lost to Follow-Up; Macrolides; Male; Onchocerciasis; Opisthorchis; Single-Blind Method; Strongyloides stercoralis; Strongyloidiasis

Strongyloides infection may result in clinical disease or confound experimental protocols that utilize non-human primates. There is presently a Strongyloides fulleborni infection rate of approximately 27% in the Tulane National Primate Research Center's breeding colonies despite the routine therapeutic and prophylactic use of ivermectin.. A study was conducted to determine if moxidectin treatment offers advantages to the intestinal parasite control program. A total of 150 rhesus macaques (Macaca mulatta) that were removed from the breeding colonies due to illness were selected for the study. The animals were randomly assigned to treatment groups with 75 receiving ivermectin and 75 receiving moxidectin. Egg counts were performed on fecal samples collected pre- and post-treatment.. Both treatments resulted in decreases in the number of eggs/g in the post-treatment sample as compared with the pre-treatment sample; however, no significant difference was found between treatment groups.. With the data demonstrating a similar efficacy in both ivermectin and moxidectin treated macaques, the benefit of moxidectin treatment relates to biosafety and topical application.

Topics: Administration, Topical; Animals; Feces; Female; Injections, Intramuscular; Ivermectin; Macaca mulatta; Macrolides; Male; Monkey Diseases; Parasite Egg Count; Specific Pathogen-Free Organisms; Strongyloides; Strongyloidiasis

Moxidectin is a frontrunner drug candidate in the treatment of strongyloidiasis. A dose of 8 mg is recommended to treat this indication, which shows a reasonably good efficacy and tolerability profile. Yet, owing to the unique life cycle of Strongyloides stercoralis (S. stercoralis) that entails internal autoinfection, a curative treatment would be desirable. Population-based pharmacometric modeling that would help to identify an ideal dosing strategy are yet lacking. The aims of this study were to (i) explore the exposure-efficacy response relationship of moxidectin in treating S. stercoralis and (ii) evaluate whether moxidectin treatment outcomes in terms of cure rates at baseline as compared to post-treatment could be optimized. Our pharmacodynamic model suggests high predictive power (area under the concentration time curve-receiver operating characteristic [AUC-ROC] 0.817) in the probability of being cured by linking an exposure metric (i.e., AUC

Topics: Animals; Humans; Macrolides; Strongyloides stercoralis; Strongyloidiasis; Treatment Outcome

Moxidectin is a promising candidate for addition to the lean repertoire of drugs against neglected tropical diseases (NTD) including strongyloidiasis. Pharmacokinetic (PK) and -dynamic studies are required to support its clinical development. Microsampling approaches enable PK studies in the challenging environments where NTDs are most prevalent, due to simplified collection and processing. We developed a liquid chromatography tandem mass spectrometry method for the sensitive quantification of moxidectin in human blood obtained by capillary sampling with the microsampling device Mitra® compared to blood and plasma obtained by venous sampling. Sample preparation consisted of protein precipitation, evaporation and reconstitution and also included phospholipid filtration for blood and plasma. Moxidectin was detected by multiple reaction monitoring (640.4 → 528.5 m/z) using a Luna C8(2) (30 × 2.0 mm, 3 µm particle size, 100 Å) analytical column with a gradient program of 6 min duration. Validation was performed with respect to accuracy, precision, sensitivity, selectivity, linearity, stability, recovery, and haematocrit influence with a limit of quantification of 0.5 and 2.5 ng/mL, for venous and capillary blood respectively. Moxidectin was stable up to 2 months at storage condition (blood and plasma: -20 °C, microsamples: room temperature), 3 cycles of temperature shift, for at least 4 h on the bench-top and 24 h in the autosampler (4 °C). Deviations of inter- and intra-assay accuracy and precision were smaller than 12.6% and recoveries were in the range of 80.7-111.2%. The method was applied to samples obtained from nine Strongyloides stercoralis-infected adults from northern Laos. A good agreement in the time-concentration profiles of moxidectin and a high consistency in PK parameters was found between the different matrixes and sampling strategies: e.g. identical time to reach maximal concentration of 4.0 h and a similar maximal concentration of 83.9-88.5 ng/mL of moxidectin. The simple and practical capillary procedure using Mitra® microsampling has been demonstrated to be suitable for PK studies of moxidectin and will pave the way for future PK studies.

Topics: Adult; Animals; Anthelmintics; Chromatography, Liquid; Humans; Laos; Linear Models; Macrolides; Reproducibility of Results; Sensitivity and Specificity; Strongyloides stercoralis; Strongyloidiasis; Tandem Mass Spectrometry

Topics: Animals; Humans; Ivermectin; Macrolides; Strongyloides stercoralis; Strongyloidiasis

Routine faecal examination of a herd of weaned male goats revealed heavy infections with gastrointestinal strongyles (GIS) and Strongyloides sp. Moxidectin (routinely dosed at 0.3 mg·kg

Topics: Age Factors; Albendazole; Animals; Anthelmintics; Disease Outbreaks; Drug Resistance; Feces; Goat Diseases; Goats; Guadeloupe; Ivermectin; Levamisole; Macrolides; Male; Parasite Egg Count; Strongyloides; Strongyloidiasis; Treatment Outcome; Tropical Climate