In:
PLOS Neglected Tropical Diseases, Public Library of Science (PLoS), Vol. 16, No. 3 ( 2022-3-10), p. e0010219-
Abstract:
To accelerate the progress towards onchocerciasis elimination, a macrofilaricidal drug that kills the adult parasite is urgently needed. Emodepside has shown macrofilaricidal activity against a variety of nematodes and is currently under clinical development for the treatment of onchocerciasis. The aims of this study were i) to characterize the population pharmacokinetic properties of emodepside, ii) to link its exposure to adverse events in healthy volunteers, and iii) to propose an optimized dosing regimen for a planned phase II study in onchocerciasis patients. Methodology / Principal findings Plasma concentration-time profiles and adverse event data were obtained from 142 subjects enrolled in three phase I studies, including a single-dose, and a multiple-dose, dose-escalation study as well as a relative bioavailability study. Nonlinear mixed-effects modeling was used to evaluate the population pharmacokinetic properties of emodepside. Logistic regression modeling was used to link exposure to drug-related treatment-emergent adverse events (TEAEs). Emodepside pharmacokinetics were well described by a transit-absorption model, followed by a 3-compartment disposition model. Body weight was included as an allometric function and both food and formulation had a significant impact on absorption rate and relative bioavailability. All drug-related TEAEs were transient, and mild or moderate in severity. An increase in peak plasma concentration was associated with an increase in the odds of experiencing a drug-related TEAE of interest. Conclusions/Significance Pharmacokinetic modeling and simulation was used to derive an optimized, body weight-based dosing regimen, which allows for achievement of extended emodepside exposures above target concentrations while maintaining acceptable tolerability margins.
Type of Medium:
Online Resource
ISSN:
1935-2735
DOI:
10.1371/journal.pntd.0010219
DOI:
10.1371/journal.pntd.0010219.g001
DOI:
10.1371/journal.pntd.0010219.g002
DOI:
10.1371/journal.pntd.0010219.g003
DOI:
10.1371/journal.pntd.0010219.g004
DOI:
10.1371/journal.pntd.0010219.g005
DOI:
10.1371/journal.pntd.0010219.t001
DOI:
10.1371/journal.pntd.0010219.t002
DOI:
10.1371/journal.pntd.0010219.t003
DOI:
10.1371/journal.pntd.0010219.s001
DOI:
10.1371/journal.pntd.0010219.s002
DOI:
10.1371/journal.pntd.0010219.s003
DOI:
10.1371/journal.pntd.0010219.s004
DOI:
10.1371/journal.pntd.0010219.s005
DOI:
10.1371/journal.pntd.0010219.s006
DOI:
10.1371/journal.pntd.0010219.s007
DOI:
10.1371/journal.pntd.0010219.s008
DOI:
10.1371/journal.pntd.0010219.s009
DOI:
10.1371/journal.pntd.0010219.s010
DOI:
10.1371/journal.pntd.0010219.s011
DOI:
10.1371/journal.pntd.0010219.s012
DOI:
10.1371/journal.pntd.0010219.s013
DOI:
10.1371/journal.pntd.0010219.s014
DOI:
10.1371/journal.pntd.0010219.s015
Language:
English
Publisher:
Public Library of Science (PLoS)
Publication Date:
2022
detail.hit.zdb_id:
2429704-5
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