Dataset Information

Characterization of the Population Pharmacokinetics of Moxidectin in Adults Infected with Strongyloides Stercoralis: Support for a Fixed-Dose Treatment Regimen.

ABSTRACT:

Background

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.

Methods

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).

Results

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.

Conclusion

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.

Trial registration

Registered at ClinicalTrials.gov (NCT04056325).

SUBMITTER: Smit C

PROVIDER: S-EPMC8761718 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BACKGROUND: Differences between noninfective first-stage (L1) and infective third-stage (L3i) larvae of parasitic nematode Strongyloides stercoralisat the molecular level are relatively uncharacterized. DNA microarrays were developed and utilized for this purpose. METHODS AND FINDINGS: Oligonucleotide hybridization probes for the array were designed to bind 3571 putative mRNA transcripts predicted by analysis of 11,335 expressed sequence tags (ESTs) obtained as part of the Nematode EST project. RNA obtained from S. stercoralis L3i and L1 was co-hybridized to each array after labeling the individual samples with different fluorescent tags. Bioinformatic predictions of gene function were developed using a novel cDNA Annotation System software. We identified 967 differentially expressed genes (457 L3i-biased; 510 L1-biased) having greater than two-fold expression differences and p < 0.01. Based on functional analysis, L1s have a larger number of genes putatively involved in transcription (p = 0.0158), and L3is have higher expression of stress-related genes (such as putative heat shock proteins dnj-12, daf-21, dnj-10). Genes with products that have been shown to be immunoreactive in S. sterocoralis-infected humans (SsIR and NIE) were additionally found to be L3i biased. Unique and abundant L3i contigs of interest included S. stercoralis orthologs of cytochrome oxidase ucr 2.1, daf-12, and daf-21, which may be potential chemotherapeutic targets. The S. stercoralis ortholog of fatty acid and retinol binding protein-1, successfully used in a vaccine against Ancylostoma ceylanicum, was identified among the top 25 most L3i-biased genes. The sperm-containing glycoprotein domain, utilized in a vaccine against the nematode Cooperia punctata, was exclusively found in the L3i group and may be a valuable S. stercoralis target of interest. Conclusions A new DNA microarray tool for the examination of S. stercoralis biology has been developed and provides new and valuable insights regarding differences between infective and noninfective S. stercoralis larvae. Potential therapeutic and vaccine targets were identified for further study.