Drug development for the treatment of onchocerciasis: Population pharmacokinetic and adverse events modeling of emodepside

Abstract

Background 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.

Ivermectin and doxycycline treatments against Onchocerciasis: Adaptations and impact among semi-nomadic population in Massangam Health District, Cameroon

“…The macrofilaricidal impact of doxycycline makes it superior to moxidectin and ivermectin both of which require repeated rounds over a long period to allow macrofilaria to die. Other macrofilaricidal drugs are being developed [ 28 , 29 ] and once a better one is found, it can be used in place of doxycycline. Doxycycline is part of WHO [ 4 ] arsenal of alternative treatments and so we prefer piloting it in programme setting.…”

Albatrellus confluens (Alb. & Schwein.) Kotl. & Pouz.: Natural Fungal Compounds and Synthetic Derivatives with In Vitro Anthelmintic Activities and Antiproliferative Effects against Two Human Cancer Cell Lines

“…The column was monitored by UV lamp (254 and 366 nm). Fractions of 35 mL were collected as follows: [(1-6), n-hexane-EtOAc (90:10)] [ (7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24), n-hexane-EtOAc (8:2)], [ (25)(26)(27)(28)(29), n-hexane-EtOAc (7:3)], [ (30), n-hexane-EtOAc (6:4)], [ (31), n-hexane-EtOAc (1:1)], [ (32), n-hexane-EtOAc (4:6)], [ (33), n-hexane-EtOAc (3:7)], [ (34), n-hexane-EtOAc (2:8)] [ (35), n-hexane-EtOAc (1:9)], [(36), EtOAc-MeOH (9:1)] [(37), MeOH (100%)]. These fractions were pooled according to their TLC profiles into 10 subfractions F1 to F10 as follows: F1 (1-3; 0.05 g), F2 (4-7; 2.13 g), F3 (8-10; 0.24 g), F4 (11-13; 0.04 g), F5 (14-18; 0.04 g), F6 (19-23; 1.96 g), F7 (24-28; 0.39 g), F8 (29-31; 0.12 g), F9 (32-35; 0.06 g), and F10 (36-37; 0.39 g).…”

“…Emodepside, a semisynthetic derivative of PF1022A, has shown efficacy against a variety of gastrointestinal nematodes in animals including but not limited to H. contortus (sheep), Heterakis spumosa (mice), Cooperia oncophora (cattle), and Ascaris suum (pigs) [19]. Emodepside is currently under clinical development for the treatment of onchocerciasis [20]. A study has shown that ten species of gilled fungi including the oyster mushroom Pleurotus ostreatus attack and consume nematodes [21].…”