Systems Pharmacology Modelling of Ivermectin Resistance Evolution in Haemonchus contortus Populations in North Central Nigerian Small Ruminants

Ivermectin resistance in Haemonchus contortus represents an existential threat to small ruminant production across Nigeria, and its evolutionary trajectory in North Central states including Kwara, Kogi, and Nassarawa, where anthelmintic use is intensive, remains inadequately modelled. Systems pharmacology integrates pharmacokinetic-pharmacodynamic modelling with population genetics to predict resistance evolution under defined selection pressure scenarios. This study developed and validated a systems pharmacology model of ivermectin resistance evolution in H. contortus populations from small ruminant farms in the North Central zone. Resistance phenotyping was performed by larval development assay and egg hatch assay in 120 parasite isolates from 40 farms. Candidate resistance alleles in glutamate-gated chloride channel genes were characterised by deep amplicon sequencing in 80 isolates. Ivermectin pharmacokinetic data were generated in 30 Yankasa sheep by validated HPLC. A deterministic mathematical model integrating drug exposure, heterozygous fitness costs, and allele frequency dynamics was constructed and parameterised with field data. Monte Carlo simulation was used to project resistance allele frequency under five alternative dosing regimen and refugia management scenarios over 20 years. Under current recommended dosing without refugia management, full resistance was projected within 8 to 12 years. Targeted selective treatment based on faecal egg count and maintenance of refugia reduced resistance progression to 18 to 24 years. These findings provide quantitative evidence for urgently adopting targeted selective treatment strategies in North Central Nigerian small ruminant production and establish a modelling framework applicable to other anthelmintics and geographic zones. Keywords: ivermectin resistance, Haemonchus contortus, systems pharmacology, mathematical modelling, North Central Nigeria.