PBPK modeling of ivermectin ‐ considerations for the purpose of developing alternative routes to optimize its safety profile

AbstractAlthough single-dose ivermectin has been widely used in mass-drug administration (MDA) programs for onchocerciasis and lymphatic filariasis for many years, ivermectin may have utility as an endectocide with mosquito-lethal effects at dosages greater and longer than those used to treat helminths. The final PBPK model for ivermectin described here was able to capture, with reasonable accuracy, observed plasma drug concentration-time profiles and exposures of ivermectin after a single oral dose of the drug in healthy male (dose range 6 to 30 mg) and female subjects, in both fasted and fed states, in African patients with onchocerciasis (150 μg/kg) and in African children. The PBPK model can be used for further work on lactation, pediatric dosing (considering CYP3A4 and Pg-p ontogenies), pregnancy, especially if non-standard doses will be used. The key findings of our study indicate that absorption of ivermectin may be highly dependent on bile micelle mediated solubility. The drug is highly lipophilic and permeable, and its plasma exposure appears to be associated with the BMI of an individual. These are all factors that need to be considered when extrapolating to more complex oral formulations or alternative routes of administra tion. Administering lower doses over a longer period may attenuate the dependence on bile micelle mediated solubility. With relevant inputs, the verified PBPK model developed here could be used to simulate plasma exposures following administrati...
Source: CPT: Pharmacometrics and Systems Pharmacology - Category: Drugs & Pharmacology Authors: Tags: REVIEW Source Type: research