Population pharmacokinetics and exposure-response analysis of tribendimidine to improve treatment for children with hookworm infection

Tribendimidine has been successful in treating hookworm infections and may serve as alternative to albendazole should resistance arise. Our aims were to (i) characterize the pharmacokinetics (PK) of tribendimidine's primary metabolite deacetylated amidantel (dADT) and secondary metabolite, acetylated derivative of amidantel (adADT) in school-aged children and adolescents, (ii) link exposure to efficacy against hookworm, and (iii) evaluate whether tribendimidine pharmacotherapy in children could be further improved. First, a population PK model was developed based on dried-blood-spot samples collected in 155 school-aged children and adolescents with hookworm infections, following tribendimidine doses ranging from 100-400 mg. Second, an exposure-response analysis was conducted to link the active metabolite dADT to cure rates (CRs) and egg reduction rates (ERRs). Third, simulations were performed to identify a treatment strategy associated with >90% CRs. A two-compartmental model with transit compartments describing observed delay in absorption adequately described PK data of dADT and adADT. Allometric scaling was included to account for growth and development. The absorption rate was 56% lower with 200-mg tablets compared with 50 mg tablets, while the extent of absorption remained unaffected. The identified Emax models linking dADT exposure to ERRs and CRs showed shallow curves, as increasing exposure leads to marginal efficacy increase. Combination therapy should be considered as a 12-fold higher dose would be needed to achieve 95% ERRs and CRs >90% with tribendimidine alone. Further studies are warranted to evaluate safety of higher tribendimidine doses and combination therapies with other anthelmintic agents to improve treatment strategy for children with hookworm infection.